Novel amide compounds and medications containing the same technical field

ABSTRACT

The present invention provides to a novel compound having an ACAT inhibiting activity. 
 
The present invention relates to compounds represented by formula (I)  
                 
wherein represents an optionally substituted divalent residue such as benzene, pyridine, cyclohexane or naphthalene, or a group, Het represents a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, such as a monocyclic group, a polycyclic group or a group of a fused ring, X represents —NH—, an oxygen atom or a sulfur atom, 
         Y represents —NR 4 —, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone,    Z represents a single bond or —NR 5 —,    R 4  represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group,    R 5  represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group, and n is an integer of from 1 to 15, or salts or solvates thereof, and a pharmaceutical composition containing at least one of these compounds.

TECHNICAL FIELD

The present invention relates to novel amide compounds and medications containing the same. More specifically, the present invention relates to compounds represented by the the formula (I)

-   -   wherein     -   represents an optionally substituted divalent residue such as         benzene, pyridine, cyclohexane or naphthalene, or a group,

Het represents a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, such as a monocyclic group, a polycyclic group or a group of a fused ring,

-   -   X represents —NH—, an oxygen atom or a sulfur atom,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group, and     -   n is an integer of from 1 to 15,         or salts or solvates thereof, and a pharmaceutical composition         containing these compounds.

Specifically, the preent invention relates to compounds represented by the the formula (IA)

-   -   wherein     -   represents an optionally substituted divalent residue such as         benzen or pyridine,     -   Py represents an optionally substituted pyridyl or pyrimidyl         group,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,and     -   n is an integer of from 1 to 15,     -   or salts or solvates thereof, and a pharmaceutical composition         containing these compounds.

More specifically, the present invention relates to compounds represented by the formula (II)

-   -   wherein     -   X represents —NH—, an oxygen atom or a sulfur atom,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   Py represents an optionally substituted pyridyl or pyrimidyl         group, and     -   n is an integer of from 1 to 15,         or salts or solvates thereof, and a pharmaceutical composition         containing these compounds.

BACKGROUND ART

In recent years, hyperlipemia and arteriosclerosis derived therefrom have been rapidly increased with the change to western eating habits with high-calory and high-cholesterol foods based on the higher level of life and with the advance of age of the population, and this has been one of social problems. The conventional pharmacotherapy of hyperlipemia and arteriosclerosis has mainly put stress on the decrease in blood lipid that causes these diseases, and the lesion of the arteriosclerosis itself has not been treated as a target. Acyl coenzyme A cholesterol acyltransferase (ACAT) is an enzyme that catalyzes synthesis from cholesterol to cholesterol ester, and plays a vital role in metabolism of cholesterol and absorption thereof in digestive organs. Inhibition of the ACAT enzyme that catalyzes esterification of free cholesterol in epithelial cells of the small intestine results in inhibition of absorption of cholesterol from the intestine, and inhibition of synthesis of cholesterol ester in the liver based on the ACAT inhibition results in suppression of secretion of VLDL from the liver to the blood. These results are considered to lead to an activity of decreasing blood cholesterol. Most of conventional ACAT inhibitors have been expected to exhibit an activity of decreasing blood cholesterol as an antihyperlipemic agent by acting on the ACAT enzymes in the small intestine and the liver.

For example, as an ACAT inhibitor, the specification of U.S. Pat. No. 4,716,175 describes 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, and European Patent No. 372,445 describes N′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea. However, most of the conventional ACAT inhibitors have put stress on an activity of decreasing blood cholesterol as an antihyperlipemic agent, and the administration thereof at a high dose for exhibiting its activity has often caused side effects such as intestinal bleeding, intestinal disorders, diarrhea, hepatopathy and the like at the stage of a clinical test, making difficult the clinical development thereof.

The arteriosclerosis is inherently a characteristic lesion such as intima hypertrophy and lipidosis of the blood vessel. According to the recent studies, suppression of foamation of macrophages that play a main role in formation of the arteriosclerosis lesion has been expected to lead to regression of the arteriosclerosis lesion itself. Foam cells derived from macrophages (cholesterol ester is stored in cells as fat droplets) have been observed in the gruel arteriosclerosis lesion, and the foamation of macrophages is deemed to deeply participate in the progression of the lesion. Further, it has been reported that the ACAT activity in the blood vessel wall in the arteriosclerosis lesion site is increased and cholesterol ester is stored in the blood vessel wall (refer to Gillease, J. et al., Exp. Mole. Pathol., 44, 329-339 (1986)].

The inhibition of esterification of cholesterol with an ACAT inhibitor results in formation of free cholesterol in cells, and this free cholesterol is removed with high-density lipoprotein (HDL), transferred to the liver (inversely transferred with HDL), and metabolized. Accordingly, suppression of storage of cholesterol ester in the lesion site is expected. As a result, it is considered to provide a direct anti-arteriosclerotic activity. There is a report that ACAT includes two types, a type present in the small intestine and a type present in the blood vessel wall (Kinunen M. et al., Biochemistry, 27, 7344-7350 (1988)]. However, many of the past researches on the ACAT inhibitor have been conducted using an enzyme of a type present in the small intestine and the liver [Tomoda Eiichi et al., J. Antibiotics, 47, 148-153 (1994)].

The present inventors considered that medications which selectively inhibit an ACAT enzyme of a type present in the blood vessel wall can be those for treating arteriosclerosis that give less side effects, and have conducted synthesis and researches of such inhibitors.

The present inventors continued studies for achieving this object, and found in advance that compounds represented by the formula (IV)

-   -   wherein     -   represents an optionally substituted divalent residue such as         benzene, pyridine, cyclohexane or naphthalene or a group,     -   Ar represents an optionally substituted aryl group     -   X represents —NH—, an oxygen atom or a sulfur atom,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group, and     -   n is an integer of from 0 to 15,         or salts or solvates thereof, and compounds represented by the     -   wherein     -   represents an optionally substituted divalent residue such as         benzene, pyridine, cyclohexane or naphthalene, or a group,     -   Ar represents an optionally substituted aryl group,     -   X represents —NH—, an oxygen atom or a sulfur atom,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   l is an integer of from 0 to 15,     -   m is an integer of 2 or 3, and     -   n is integer of from 0 to 3,         or salts or solvates thereof have an excellent ACAT inhibitory         activity, and they applied the same for patents (Japanese Patent         Application Nos. 88,660/1997, 90,146/1997 and 149,892/1997).

Further, as compounds similar to the compounds represented by the formula (I), 3-(benzothiazol-2-ylthio)-N-(phenyl)propanamide is disclosed in J. Chem. Eng. Data, 27, 207 (1982), and 3-(benzoxazol-2-ylthio)-N-(phenyl)propanamide in Fungitsidy, Ed. Melnikov, N. N. Izd. FanUzb. SSR: Tashkent, USSR. 82-88 (1980). However, these compounds are not only those in which an amide moiety is a phenyl group, but also these documents are totally devoid of the description that the compounds have an ACAT inhibitory activity.

Thus, the present inventors found that the compounds represented by the formula (IV) or (V) have an organ-selective ACAT inhibitory activity and an intracellular cholesterol transfer inhibitory activity, and that these are useful as an antihyperlipemic agent having an activity of decreasing blood cholesterol and as an agent for preventing and treating arteriosclerosis having a macrophage foamation inhibitory activity.

However, the compounds represented by these formulas (IV) and (V) did not necessarily have a sufficient activity, nor was the organ-selectivity satisfactory.

Under these circumstances, the present inventors have conducted further investigations to develop an ACAT inhibitor having a superior ACAT inhibitory activity, and have consequently found that the compounds represented by the formula (I) are useful ACAT inhibitors which conquer the above-mentioned defects. This finding has led to the completion of the present invention.

DISCLOSURE OF INVENTION

The present invention is to provide compounds represented by the formula (I)

-   -   wherein     -   represents an optionally substituted divalent residue such as         benzene, pyridine, cyclohexane or naphthalene, or a group     -   Het represents a 5- to 8-membered, substituted or unsubstituted         heterocyclic group containing at least one heteroatom selected         from the group consisting of a nitrogen atom, an oxygen atom and         a sulfur atom, such as a monocyclic group, a polycyclic group or         a group of a fused ring,     -   X represents —NH—, an oxygen atom or a sulfur atom,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group, and     -   n is an integer of from 1 to 15,         or salts or solvates thereof.

Further, the present invention is to provide a pharmaceutical composition containing at least one type selected from the compounds represented by the formula (I), and the salts and the solvates thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier.

Still further, the present invention is to provide an ACAT inhibitor, an intracellular cholesterol transfer inhibitor, a blood cholesterol depressant or a macrophage foamation suppressant containing at least one type selected from the compounds represented by the formula (I), and the salts and the solvates thereof in a therapeutically effective amount, and a pharmaceutically acceptable carrier. That is, the present invention is to provide a medication for treating or preventing diseases such as hyperlipemia, arteriosclerosis, cervical and cerebral arteriosclerosis, cerebrovascular accidents, ischemic heart disease, coronary arteriosclerosis, nephrosclerosis, arteriosclerotic nephrosclerosis, arteriolonephrosclerosis, malignant nephrosclerosis, ischemic intestinal disease, acute occlusion of mesenteric vessel, chronic mesenteric angina, ischemic colitis, aortic aneurysm and arteriosclerosis obliterans (ASO), this medication containing at least one type selected from the compounds represented by the formula (I), and the salts and the solvates thereof, and a pharmaceutically acceptable carrier, as well as a therapeutic method using the same.

BEST MODE FOR CARRYING OUT THE INVENTION

As preferable examples of the compounds represented by the the formula (IA)

-   -   wherein     -   represents an optionally substituted divalent residue such as         benzen or pyridine,     -   Py represents an optionally substituted pyridyl or pyrimidyl         group,     -   X represents —NH—, an oxygen atom or a sulfur atom,     -   Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide         or a sulfone,     -   Z represents a single bond or —NR₅—,     -   R₄ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,     -   R₅ represents a hydrogen atom, a lower alkyl group, an aryl         group or an optionally substituted silyl lower alkyl group,and     -   n is an integer of from 1 to 15,         or salts or solvates thereof, and a pharmaceutical composition         containing these compounds can be mentioned.

As more preferable examples of the compounds represented by the formula (I) in the present invention, the compounds represented by the formula (II)

-   -   wherein Py represents an optionally substituted pyridyl or         pyrimidyl group, and the other substituents are the same as         described in the above-mentioned the formula (I),         and the salts or the solvates thereof can be mentioned.

As further preferable examples of the compounds represented by the formula (I) in the present invention, the compounds represented by the formula (III)

-   -   wherein     -   W represents ═CH— or ═N—, and     -   R₁, R₂ and R₃ are the same or different, and each represents a         hydrogen atom, a lower alkyl group, a lower alkoxy group, a         halogen atom, a hydroxyl group, a phosphate group, a sulfonamide         group, a lower alkylthio group or an optionally substituted         amino group, or two of R₁, R₂ and R₃ together form an         alkylenedioxide group.

The substituent Het of the compounds represented by the formula (I) in the present invention is a 5- to 8-membered, substituted or unsubstituted heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. This cyclic group may be a monocyclic group, a polycyclic group in which the heterocyclic groups are bound to each other or bound to a carbon ring such as a 6-membered aromatic ring either directly or through a carbon chain, or a group of a fused ring in which the heterocyclic groups are fused to each other or to a carbon ring such as a 6-membered aromatic ring. Among these heterocyclic groups, a 5- to 8-membered heterocyclic group, preferably a 5- or 6-membered heterocyclic group, containing one or two nitrogen atoms is preferable. Preferable examples of the substituent Het include a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidyl group, a substituted or unsubstituted indolyl group, and a substituted or unsubstituted quinolyl group. A substituted or unsubstituted pyridyl group, and a substituted or unsubstituted pyrimidyl group are further preferable.

These heterocyclic groups may be unsubstituted, but have preferably one or more substituents. The substituent of these heterocyclic groups is not particularly limited unless the ACAT inhibitory activity of the present invention is impaired. Preferable examples thereof include an amino group substituted with a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylcarbonyl group, a halogen atom, an amino group or a lower alkyl group; a substituted or unsubstituted aryl group such as a phenyl group or a naphthyl group; and a substituted or unsubstituted aralkyl group such as a benzyl group or a phenetyl group. Further, two substituents may be bound to form an alkylenedioxy group such as a methylenedioxy group.

As the lower alkyl group, a linear or branched alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms is preferable. Especially preferable examples thereof include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl and n-hexyl groups.

As the lower alkyl group in the lower alkoxy group, the lower alkylthio group and the lower alkylcarbonyl group, the above-mentioned linear or branched alkyl group having from 1 to 10 carbon atoms, preferably from 1 to 6 carbon atoms is preferable. Examples thereof include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl groups.

Preferable examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms.

As the aryl group, an aryl group having from 6 to 20 carbon atoms, preferably from 6 to 10 carbon atoms is mentioned. This aryl group may be unsubstituted or substituted with the above-mentioned lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylcarbonyl group, halogen atom, amino group or amino group substituted with the lower alkyl group. Preferable examples of the aryl group include phenyl, naphthyl, 2-methoxyphenyl and 4-methylthiophenyl groups.

The aralkyl group is an aralkyl group having from 7 to 20 carbon atoms, preferably from 7 to 12 carbon atoms. This aralkyl group may be unsubstituted or substituted with the above-mentioned lower alkyl group, lower alkoxy group, lower alkylthio group, lower alkylcarbonyl group, halogen atom, amino group or amino group substituted with the lower alkyl group. Preferable examples of the aralkyl group include benzyl, phenetyl and 4-methylbenzyl groups.

Examples of the substituent in the substituted amino group include the above-mentioned lower alkyl, lower alkylcarbonyl, aryl and aralkyl groups, and the number of the substituent in the amino group may be 1 or 2. Preferable examples of the substituted amino group include methylamino, ethylamino, dimethylamino, diethylamino, acetylamino and benzylamino groups.

The alkylene group of the alkylenedioxy group is a linear or branched alkylene group having from 1 to 10 carbon atoms, preferably from 1 to 5 carbon atoms. Preferable examples thereof include methylenedioxy and ethylenedioxy groups.

As the preferable Het group, a group represented by the formula (VI) is mentioned.

-   -   wherein W, R₁, R₂ and R₃ are as defined above.

Preferable examples of the Het group include

-   -   2-methylthio-3-pyridyl,     -   2-ethylthio-3-pyridyl,     -   2-(iso-propylthio)-3-pyridyl,     -   2-methoxy-3-pyridyl,     -   2-chloro-3-pyridyl,     -   2-methylthio-4-methyl-3-pyridyl,     -   2-ethylthio-4-methyl-3-pyridyl,     -   2-(iso-propylthio)-4-methyl-3-pyridyl,     -   2-methoxy-4-methyl-3-pyridyl,     -   2,6-bis(methylthio)-3-pyridyl,     -   2,6-bis(ethylthio)-3-pyridyl,     -   2,6-bis(iso-propylthio)-3-pyridyl,     -   2-methylthio-6-methoxy-3-pyridyl,     -   2-ethylthio-6-methoxy-3-pyridyl,     -   2-(iso-propylthio)-6-methoxy-3-pyridyl,     -   2-methylthio-6-methyl-3-pyridyl,     -   2-ethylthio-6-methyl-3-pyridyl,     -   2-(iso-propylthio)-6-methyl-3-pyridyl     -   2,6-dimethoxy-3-pyridyl,     -   2-methoxy-6-methyl-3-pyridyl,     -   2-methyl-6-methylthio-3-pyridyl,     -   2-methyl-6-ethylthio-3-pyridyl,     -   2-methyl-6-(iso-propylthio)-3-pyridyl,     -   2-methyl-6-methoxy-3-pyridyl,     -   2,6-dimehtyl-3-pyridyl,     -   2,6-diethyl-3-pyridyl,     -   2,4-bismethylthio-6-methyl-3-pyridyl,     -   2,4-bisethylthio-6-methyl-3-pyridyl,     -   2,4-bis(iso-propylthio)-6-methyl-3-pyridyl,     -   2,4-dimethoxy-6-methyl-3-pyridyl,     -   2,4,6-trimethyl-3-pyridyl,     -   4-ethyl-2,6-dimethyl-3-pyridyl,     -   2,4-dichloro-6-methyl-3-pyridyl,     -   4,6-bis(methylthio)-5-pyrimidyl,     -   4,6-bis(ethylthio)-5-pyrimidyl,     -   4,6-bis(iso-propylthio)-5-pyrimidyl,     -   4,6-dimethoxy-5-pyrimidyl,     -   4,6-dichloro-2-methyl-5-pyrimidyl,     -   4,6-bis(dimethylamino)-5-pyrimidyl,     -   4,6-bismethylthio-2-methyl-5-pyrimidyl,     -   2,4,6-trimethoxy-5-pyrimidyl     -   4-methyl-6-methyltio-3-pyridyl,     -   5-methylthio-2-pyridyl,     -   2,4,6-tris(methylthio)-5-pyrimidyl groups and so on.

The substituent

in the compounds represented by the the formula (I) in the present invention is a divalent group adjacent the azole ring which is formed with two carbon atoms constituting the azole ring. It is preferably an optionally substituted divalent group such as benzene, pyridine, cyclohexane or naphthalene, or a group as follows.

An optionally substituted divalent residue such as benzen or pyridine is preferable. These divalent groups may have a substituent. Examples of the substituent include the above-mentioned lower alkyl group, lower alkoxy group, lower alkylsulfonyl group lower alkylthio group, lower alkylcarbonyl group, halogen atom, amino group, amino group substituted with the lower alkyl group, substituted or unsubstituted aryl group such as the phenyl group or the naphthyl group, and substituted or unsubstituted aralkyl group such as the benzyl group or the phenetyl group. Further, the two substituents may be bound to form an alkylenedioxy group such as a methylenedioxy group.

The substituent X in the compounds represented by the formula (I) in the present invention represents —NH—, an oxygen atom or a sulfur atom, and forms, together with the above-mentioned substituent, an azole ring such as imidazole, oxazole or thiazole.

Further, the substituent Y in the compounds represented by the formula (I) of the present invention represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone, and the substituent R₄ of the nitrogen atom represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group. The lower alkyl group or the aryl group as the substituent R₄ is as mentioned above. Examples thereof include methyl, ethyl and phenyl groups. The lower alkyl group of the optionally substituted silyl lower alkyl group as the substituent R₄ may be the above-mentioned group. Examples of the substituent of the silyl lower alkyl group include the above-mentioned lower alkyl, aryl and aralkyl groups. Preferable examples thereof include trimethylsilylmethyl and dimethylphenylsilylmethyl groups.

As the substituent Y, a sulfur atom is preferable.

The substituent Z in the compounds represented by the formula (I) of the present invention represents a single bond or —NR₅—, and the substituent R₅ of the nitrogen atom represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group. Examples of these substituents are the above-mentioned groups.

The number n of recurring units in the compounds represented by the formula (I) in the present invention is an integer of from 1 to 15, preferably an integer of from 1 to 9. As the recurring unit, a methylene group is mentioned in the formula (I). The methylene group may have a substituent or one or more methylene units may be substituted with a heteroatom such as a nitrogen atom, an oxygen atom or a sulfur atom unless the ACAT inhibitory activity of the present invention is impaired.

The substituents X, Y, Z and the recurring unit in the compounds represented by the formula (II) in the present invention are the above-mentioned ones. The substituent Py represents an optionally substituted pyridyl or pyrimidyl group. The substituent of the pyridyl or pyrimidyl group is not particularly limited unless the ACAT inhibitory activity of the present invention is impaired. The group represented by the formula (VI) is preferable.

The substituents X, Y, Z and the recurring unit in the compounds represented by the formula (III) in the present invention are the above-mentioned ones. The substituent W represents a carbon atom or a nitrogen atom, and forms a pyridine or pyrimidine ring. Further, the substituents R₁, R₂ and R₃ are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a phosphate group, a sulfonamide group, a lower alkylthio group or an optionally substituted amino group, or two of R₁, R₂ and R₃ together form an alkylenedioxy group. Of these groups, the lower alkyl group, the lower alkoxy group, the halogen atom, the lower alkylthio group, the optionally substituted amino group and the alkylenedioxy group are the above-mentioned ones. Preferable examples of R₁, R₂ and R₃ include methyl, ethyl, iso-propyl, methoxy, ethoxy and iso-propoxy groups, chlorine, and methylthio, ethylthio, iso-propylthio and dimethylamino groups. The site of the pyridine ring or the pyrimidine ring bound to the adjacent nitrogen atom is not particularly limited either unless the ACAT inhibitory activity of the present invention is impaired.

The salts of the compounds represented by the formula (I), (II) or (III) in the present invention are not particularly limited unless the ACAT inhibitory activity of the present invention is impaired. Acid addition salts or base addition salts can be used as required. Preferable examples of the acid addition salts include inorganic acid salts such as a hydrochloride, a sulfate, a nitrate and a phosphate; and organic acid salts such as a methanesulfonate, a maleate, a fumarate and a citrate.

Further, the solvates of the compounds represented by the formula (I), (II) or (III) in the present invention are products to which solvents used in the production, the purification or the like, such as water, alcohol and the like are added, and are not particularly limited unless they have an adverse effect on the ACAT inhibitory activity. As the solvates, hydrides are preferable.

A process for producing the compounds of the present invention is described below.

Compounds (I) can be produced by various known processes, and the process is not particularly limited. For example, compounds (I) can be produced according to the following reaction steps.

1. Process for Producing Compounds of the Formula (I) when the Substituent Z is a Single Bond:

A carboxylic acid represented by the formula (VII) or its reactive derivative, for example, an acid halide, is reacted with a heterocyclic amine represented by the formula (VIII) according to the following reaction formulae

wherein R₆ represents a leaving group, and R₇ represents a reactive derivative residue of a hydroxyl group or a carboxylate group, to form an amide derivative represented by the formula (IX). When the resulting compound of the formula (IX) is reacted with an azole derivative represented by the formula (X), a desired compound (I′) in which the substituent Z in the formula (I) is a single bond can be produced.

An ordinary method used in peptide synthesis can be applied to the reaction between compounds (VII) and (VIII). Examples of the leaving group R₆ in the formula (VII) include halogen atoms such as chlorine and bromine atoms. Preferable examples of the reactive derivative residue R₇ include acid anhydride residues with mesylic acid, tosylic acid, acetic acid, pivaloylic acid and the like. This reaction is described more specifically below. The desired compound can be obtained by reacting both of the compounds in a solvent in the presence of a condensation agent. As the condensation agent, for example, 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) and 1,3-dicyclohexylcarbodiimide (DCC) may be used singly, and a combination of 1-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSu) is also available. The solvent is not particularly limited. For example, dimethylformamide, methylene chloride, chloroform, tetrahydrofuran and toluene can be used either singly or in combination. The reaction conditions vary depending on a starting material to be used. Generally, the reaction is conducted at from 0 to 100° C., preferably at a temperature close to room temperature, for from 1 to 30 hours, preferably for from 10 to 20 hours. In this manner, the reaction is completed. Further, when a carbonyl halide having a high reactivity is used as compound (VII), for example, compounds (VII) and (VIII) can be reacted in the presence of a base, for example, triethylamine, 4-dimethylaminopyridine or N-methylmorpholine in a usual manner.

With respect to starting compounds (VII) and (VIII), for example, compound (VII) can be produced by a method in which a haloalkyl alcohol is oxidized into a carboxylic acid with a Jones' reagent or the like, and compound (VIII) by a method in which a nitrated heterocyclic compound is subjected to a reduction reaction such as a catalytic reduction or the like to obtain a corresponding amino heterocyclic compound, respectively.

The reaction between compounds (IX) and (X) obtained by the above-mentioned methods can be conducted in a solvent in the presence or absence of a base. As the solvent, the above-mentioned various types can be used. The base includes inorganic bases, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, and alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; and organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine and N,N-dimethylaniline.

Further, with respect to the desired compound represented by the formula (I′), according to the reaction shown by the following formula

-   -   wherein R₆ represents a leaving group, and R₇ represents a         reactive derivative residue of a hydroxyl group or a carboxylate         group, an azole derivative represented by the formula (X) is         reacted with a free carboxylic acid or an inactive substance of         a carboxylic acid as the compound represented by the         formula (VII) to obtain a carboxylic acid derivative represented         by the formula (XI). When the resulting compound represented by         the formula (XI) or its reactive derivative, for example, an         acid halide, is reacted with a heterocyclic amine derivative         represented by the formula (VIII), the desired compound (I′) in         which the substituent Z in the formula (I) is a single bond can         be produced.

The reaction between compounds (X) and (VII) can be conducted according to the second step of the above-mentioned reaction formula. The reaction in which potassium hydroxide is used as a base and ethanol as a solvent respectively is especially preferable. The reaction between the resulting compounds (XI) and (VIII) can be conducted according to the first step of the above-mentioned reaction formula.

2. Process for Producing Compounds of the Formula (I) when the Substituent Z is —NH—:

The compound represented by the formula (I) in which Z is —NH— can be produced by various processes. It is preferable to produce the same by the process shown by the following reaction formula.

-   -   wherein R₈ represents a leaving group.

The isocyanate derivative represented by the formula (XII) is reacted with the heterocyclic amine represented by the formula (VIII) to obtain an urea derivative represented by the formula (XIII). The resulting urea derivative is reacted with compound (X) to form desired compound (I″) in which the substituent Z in the formula (I) is —NH—.

With respect to the reaction between compounds (XII) and (VIII) in the first step of this reaction formula, compound (XII) is reacted with compound (VIII) in an amount of from 1 to 2 equivalents in a solvent to obtain compound (XIII). At this time, the solvent is not particularly limited. Preferable examples thereof include methylene chloride, chloroform, ether, tetrahydrofuran, toluene, xylene and dimethylformamide. The reaction proceeds in a boiling point of a solvent used from 0° C. for a reaction time of from 1 to 24 hours.

The isocyanate derivative represented by the formula (XII) is a known compound, and it can be produced by, for example, a method in which the above-mentioned carboxylic acid as compound (VII) is reacted with diphenylphospholyl azide in the presence of a base (method of Shioiri et al.), a method via an acid azide by reacting the acid halide of compound (VII) with sodium azide.

The reaction between compounds (XIII) and (X) can be conducted according to the second step of the above-mentioned reaction formula.

Further, when the substituent Z in the formula (I) is —NR₅— (wherein R₅ represents the above-mentioned groups except a hydrogen atom), the compound can be produced by replacing a nitrogen atom with the substituent R₅ at an appropriate stage.

The intermediate and the desired compound obtained in each of the above-mentioned reactions can be isolated and purified by a purification method which is ordinarily used in the synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatographies. Further, each intermediate is subjected to the subsequent step without any purification unless any trouble is caused, which is well known to those skilled in the art.

The resulting compounds (I) can be formed into salts of the present invention in a usual manner.

Further, compounds (I) can be formed into solvates with solvents such as a reaction solvent, a recrystallization solvent and the like, especially hydrides in a usual manner, which is well known to those skilled in the art.

The compounds represented by the formula (I), (II) or (III), which are obtained by the process of the present invention are shown in Tables 1 to 63 below. TABLE 1 Com- pound No.

X Y Z n Het  1

O S * 1 2-methylthio-3-pyridyl  2 ″ O S * 2 2-methylthio-3-pyridyl  3 ″ O S * 3 2-methylthio-3-pyridyl  4 ″ O S * 4 2-methylthio-3-pyridyl  5 ″ O S * 5 2-methylthio-3-pyridyl  6 ″ O S * 6 2-methylthio-3-pyridyl  7 ″ O S * 7 2-methylthio-3-pyridyl  8 ″ O S * 8 2-methylthio-3-pyridyl  9 ″ O S * 9 2-methylthio-3-pyridyl 10 ″ O S * 14  2-methylthio-3-pyridyl 11 ″ S S * 1 2-methylthio-3-pyridyl 12 ″ S S * 2 2-methylthio-3-pyridyl 13 ″ S S * 3 2-methylthio-3-pyridyl 14 ″ S S * 4 2-methylthio-3-pyridyl 15 ″ S S * 5 2-methylthio-3-pyridyl 16 ″ S S * 6 2-methylthio-3-pyridyl 17 ″ S S * 7 2-methylthio-3-pyridyl 18 ″ S S * 8 2-methylthio-3-pyridyl 19 ″ S S * 9 2-methylthio-3-pyridyl 20 ″ S S * 14  2-methylthio-3-pyridyl * Single Bond

TABLE 2 Com- pound No.

X Y Z n Het 21

NH S * 1 2-methylthio-3-pyridyl 22 ″ NH S * 2 2-methylthio-3-pyridyl 23 ″ NH S * 3 2-methylthio-3-pyridyl 24 ″ NH S * 4 2-methylthio-3-pyridyl 25 ″ NH S * 5 2-methylthio-3-pyridyl 26 ″ NH S * 6 2-methylthio-3-pyridyl 27 ″ NH S * 7 2-methylthio-3-pyridyl 28 ″ NH S * 8 2-methylthio-3-pyridyl 29 ″ NH S * 9 2-methylthio-3-pyridyl 30 ″ NH S * 14  2-methylthio-3-pyridyl 31 ″ O S * 1 2-ethylthio-3-pyridyl 32 ″ O S * 2 2-ethylthio-3-pyridyl 33 ″ O S * 3 2-ethylthio-3-pyridyl 34 ″ O S * 4 2-ethylthio-3-pyridyl 35 ″ O S * 5 2-ethylthio-3-pyridyl 36 ″ O S * 6 2-ethylthio-3-pyridyl 37 ″ O S * 7 2-ethylthio-3-pyridyl 38 ″ O S * 8 2-ethylthio-3-pyridyl 39 ″ O S * 9 2-ethylthio-3-pyridyl 40 ″ O S * 14  2-ethylthio-3-pyridyl * Single Bond

TABLE 3 Com- pound No.

X Y Z n Het 41

S S * 1 2-ethylthio-3-pyridyl 42 ″ S S * 2 2-ethylthio-3-pyridyl 43 ″ S S * 3 2-ethylthio-3-pyridyl 44 ″ S S * 4 2-ethylthio-3-pyridyl 45 ″ S S * 5 2-ethylthio-3-pyridyl 46 ″ S S * 6 2-ethylthio-3-pyridyl 47 ″ S S * 7 2-ethylthio-3-pyridyl 48 ″ S S * 8 2-ethylthio-3-pyridyl 49 ″ S S * 9 2-ethylthio-3-pyridyl 50 ″ S S * 14  2-ethylthio-3-pyridyl 51 ″ NH S * 1 2-ethylthio-3-pyridyl 52 ″ NH S * 2 2-ethylthio-3-pyridyl 53 ″ NH S * 3 2-ethylthio-3-pyridyl 54 ″ NH S * 4 2-ethylthio-3-pyridyl 55 ″ NH S * 5 2-ethylthio-3-pyridyl 56 ″ NH S * 6 2-ethylthio-3-pyridyl 57 ″ NH S * 7 2-ethylthio-3-pyridyl 58 ″ NH S * 8 2-ethylthio-3-pyridyl 59 ″ NH S * 9 2-ethylthio-3-pyridyl 60 ″ NH S * 14  2-ethylthio-3-pyridyl * Single Bond

TABLE 4 Com- pound No.

X Y Z n Het 61

O S * 1 2-(iso-propylthio)-3- pyridyl 62 ″ O S * 2 2-(iso-propylthio)-3- pyridyl 63 ″ O S * 3 2-(iso-propylthio)-3- pyridyl 64 ″ O S * 4 2-(iso-propylthio)-3- pyridyl 65 ″ O S * 5 2-(iso-propylthio)-3- pyridyl 66 ″ O S * 6 2-(iso-propylthio)-3- pyridyl 67 ″ O S * 7 2-(iso-propylthio)-3- pyridyl 68 ″ O S * 8 2-(iso-propylthio)-3- pyridyl 69 ″ O S * 9 2-(iso-propylthio)-3- pyridyl 70 ″ O S * 14  2-(iso-propylthio)-3- pyridyl 71 ″ S S * 1 2-(iso-propylthio)-3- pyridyl 72 ″ S S * 2 2-(iso-propylthio)-3- pyridyl 73 ″ S S * 3 2-(iso-propylthio)-3- pyridyl 74 ″ S S * 4 2-(iso-propylthio)-3- pyridyl 75 ″ S S * 5 2-(iso-propylthio)-3- pyridyl 76 ″ S S * 6 2-(iso-propylthio)-3- pyridyl 77 ″ S S * 7 2-(iso-propylthio)-3- pyridyl 78 ″ S S * 8 2-(iso-propylthio)-3- pyridyl 79 ″ S S * 9 2-(iso-propylthio)-3- pyridyl 80 ″ S S * 14  2-(iso-propylthio)-3- pyridyl * Single Bond

TABLE 5 Com- pound No.

X Y Z n Het 81

NH S * 1 2-(iso-propylthio)-3- pyridyl 82 ″ NH S * 2 2-(iso-propylthio)-3- pyridyl 83 ″ NH S * 3 2-(iso-propylthio)-3- pyridyl 84 ″ NH S * 4 2-(iso-propylthio)-3- pyridyl 85 ″ NH S * 5 2-(iso-propylthio)-3- pyridyl 86 ″ NH S * 6 2-(iso-propylthio)-3- pyridyl 87 ″ NH S * 7 2-(iso-propylthio)-3- pyridyl 88 ″ NH S * 8 2-(iso-propylthio)-3- pyridyl 89 ″ NH S * 9 2-(iso-propylthio)-3- pyridyl 90 ″ NH S * 14  2-(iso-propylthio)-3- pyridyl 91 ″ O S * 1 2-methoxy-3- pyridyl 92 ″ O S * 2 2-methoxy-3- pyridyl 93 ″ O S * 3 2-methoxy-3- pyridyl 94 ″ O S * 4 2-methoxy-3- pyridyl 95 ″ O S * 5 2-methoxy-3- pyridyl 96 ″ O S * 6 2-methoxy-3- pyridyl 97 ″ O S * 7 2-methoxy-3- pyridyl 98 ″ O S * 8 2-methoxy-3- pyridyl 99 ″ O S * 9 2-methoxy-3- pyridyl 100  ″ O S * 14  2-methoxy-3- pyridyl * Single Bond

TABLE 6 Com- pound No.

X Y Z n Het 101

S * 1 1 2-methoxy-3-pyridyl 102 ″ S S * 2 2-methoxy-3-pyridyl 103 ″ S S * 3 2-methoxy-3-pyridyl 104 ″ S S * 4 2-methoxy-3-pyridyl 105 ″ S S * 5 2-methoxy-3-pyridyl 106 ″ S S * 6 2-methoxy-3-pyridyl 107 ″ S S * 7 2-methoxy-3-pyridyl 108 ″ S S * 8 2-methoxy-3-pyridyl 109 ″ S S * 9 2-methoxy-3-pyridyl 110 ″ S S * 14  2-methoxy-3-pyridyl 111 ″ NH S * 1 2-methoxy-3-pyridyl 112 ″ NH S * 2 2-methoxy-3-pyridyl 113 ″ NH S * 3 2-methoxy-3-pyridyl 114 ″ NH S * 4 2-methoxy-3-pyridyl 115 ″ NH S * 5 2-methoxy-3-pyridyl 116 ″ NH S * 6 2-methoxy-3-pyridyl 117 ″ NH S * 7 2-methoxy-3-pyridyl 118 ″ NH S * 8 2-methoxy-3-pyridyl 119 ″ NH S * 9 2-methoxy-3-pyridyl 120 ″ NH S * 14  2-methoxy-3-pyridyl * Single Bond

TABLE 7 Com- pound No.

X Y Z n Het 121

O S * 1 2-chloro-3-pyridyl 122 ″ O S * 2 2-chloro-3-pyridyl 123 ″ O S * 3 2-chloro-3-pyridyl 124 ″ O S * 4 2-chloro-3-pyridyl 125 ″ O S * 5 2-chloro-3-pyridyl 126 ″ O S * 6 2-chloro-3-pyridyl 127 ″ O S * 7 2-chloro-3-pyridyl 128 ″ O S * 8 2-chloro-3-pyridyl 129 ″ O S * 9 2-chloro-3-pyridyl 130 ″ O S * 14  2-chloro-3-pyridyl 131 ″ S S * 1 2-chloro-3-pyridyl 132 ″ S S * 2 2-chloro-3-pyridyl 133 ″ S S * 3 2-chloro-3-pyridyl 134 ″ S S * 4 2-chloro-3-pyridyl 135 ″ S S * 5 2-chloro-3-pyridyl 136 ″ S S * 6 2-chloro-3-pyridyl 137 ″ S S * 7 2-chloro-3-pyridyl 138 ″ S S * 8 2-chloro-3-pyridyl 139 ″ S S * 9 2-chloro-3-pyridyl 140 ″ S S * 14  2-chloro-3-pyridyl * Single Bond

TABLE 8 Com- pound No.

X Y Z n Het 141

NH S * 1 2-chloro-3-pyridyl 142 ″ NH S * 2 2-chloro-3-pyridyl 143 ″ NH S * 3 2-chloro-3-pyridyl 144 ″ NH S * 4 2-chioro-3-pyridyl 145 ″ NH S * 5 2-chloro-3-pyridyl 146 ″ NH S * 6 2-chloro-3-pyridyl 147 ″ NH S * 7 2-chforo-3-pyridyl 148 ″ NH S * 8 2-chloro-3-pyridyl 149 ″ NH S * 9 2-chloro-3-pyridyl 150 ″ NH S * 14  2-chloro-3-pyridyl 151 ″ O S * 1 2-methylthio- 4-methyl-3-pyridyl 152 ″ O S * 2 2-methylthio- 4-methyl-3-pyridyl 153 ″ O S * 3 2-methylthio- 4-methyl-3-pyridyl 154 ″ O S * 4 2-methylthio- 4-methyl-3-pyridyl 155 ″ O S * 5 2-methylthio- 4-methyl-3-pyridyl 156 ″ O S * 6 2-methylthio- 4-methyl-3-pyridyl 157 ″ O S * 7 2-methylthio- 4-methyl-3-pyridyl 158 ″ O S * 8 2-methylthio- 4-methyl-3-pyridyl 159 ″ O S * 9 2-methylthio- 4-methyl-3-pyridyl 160 ″ O S * 14  2-methylthio- 4-methyl-3-pyridyl * Single Bond

TABLE 9 Com- pound No.

X Y Z n Het 161

S S * 1 2-methylthio-4- methyl-3-pyridyl 162 ″ S S * 2 2-methylthio-4- methyl-3-pyridyl 163 ″ S S * 3 2-methylthio-4- methyl-3-pyridyl 164 ″ S S * 4 2-methylthio-4- methyl-3-pyridyl 165 ″ S S * 5 2-methylthio-4- methyl-3-pyridyl 166 ″ S S * 6 2-methylthio-4- methyl-3-pyridyl 167 ″ S S * 7 2-methylthio-4- methyl-3-pyridyl 168 ″ S S * 8 2-methylthio-4- methyl-3-pyridyl 169 ″ S S * 9 2-methylthio-4- methyl-3-pyridyl 170 ″ S S * 14  2-methylthio-4- methyl-3-pyridyl 171 ″ NH S * 1 2-methylthio-4- methyl-3-pyridyl 172 ″ NH S * 2 2-methylthio-4- methyl-3-pyridyl 173 ″ NH S * 3 2-methylthio-4- methyl-3-pyridyl 174 ″ NH S * 4 2-methylthio-4- methyl-3-pyridyl 175 ″ NH S * 5 2-methylthio-4- methyl-3-pyridyl 176 ″ NH S * 6 2-methylthio-4- methyl-3-pyridyl 177 ″ NH S * 7 2-methylthio-4- methyl-3-pyridyl 178 ″ NH S * 8 2-methylthio-4- methyl-3-pyridyl 179 ″ NH S * 9 2-methylthio-4- methyl-3-pyridyl 180 ″ NH S * 14  2-methylthio-4- methyl-3-pyridyl * Single Bond

TABLE 10 Com- pound No.

X Y Z n Het 181

O S * 1 2-ethylthio-4-methyl-3- pyridyl 182 ″ O S * 2 2-ethylthio-4-methyl-3- pyridyl 183 ″ O S * 3 2-ethylthio-4-methyl-3- pyridyl 184 ″ O S * 4 2-ethylthio-4-methyl-3- pyridyl 185 ″ O S * 5 2-ethylthio-4-methyl-3- pyridyl 186 ″ O S * 6 2-ethylthio-4-methyl-3- pyridyl 187 ″ O S * 7 2-ethylthio-4-methyl-3- pyridyl 188 ″ O S * 8 2-ethylthio-4-methyl-3- pyridyl 189 ″ O S * 9 2-ethylthio-4-methyl-3- pyridyl 190 ″ O S * 14  2-ethylthio-4-methyl-3- pyridyl 191 ″ S S * 1 2-ethylthio-4-methyl-3- pyridyl 192 ″ S S * 2 2-ethylthio-4-methyl-3- pyridyl 193 ″ S S * 3 2-ethylthio-4-methyl-3- pyridyl 194 ″ S S * 4 2-ethylthio-4-methyl-3- pyridyl 195 ″ S S * 5 2-ethylthio-4-methyl-3- pyridyl 196 ″ S S * 6 2-ethylthio-4-methyl-3- pyridyl 197 ″ S S * 7 2-ethylthio-4-methyl-3- pyridyl 198 ″ S S * 8 2-ethylthio-4-methyl-3- pyridyl 199 ″ S S * 9 2-ethylthio-4-methyl-3- pyridyl 200 ″ S S * 14  2-ethylthio-4-methyl-3- pyridyl * Single Bond

TABLE 11 Com- pound No.

X Y Z n Het 201

NH S * 1 2-ethylthio-4-methyl-3- pyridyl 202 ib(id). NH S * 2 2-ethylthio-4-methyl-3- pyridyl 203 ib(id). NH S * 3 2-ethylthio-4-methyl-3- pyridyl 204 ib(id). NH S * 4 2-ethylthio-4-methyl-3- pyridyl 205 ib(id). NH S * 5 2-ethylthio-4-methyl-3- pyridyl 206 ib(id). NH S * 6 2-ethylthio-4-methyl-3- pyridyl 207 ib(id). NH S * 7 2-ethylthio-4-methyl-3- pyridyl 208 ib(id). NH S * 8 2-ethylthio-4-methyl-3- pyridyl 209 ib(id). NH S * 9 2-ethylthio-4-methyl-3- pyridyl 210 ib(id). NH S * 14 2-ethylthio-4-methyl-3- pyridyl 211 ib(id). O S * 1 2-(iso-propylthio)-4- methyl-3-pyridyl 212 ib(id). O S * 2 2-(iso-propylthio)-4- methyl-3-pyridyl 213 ib(id). O S * 3 2-(iso-propylthio)-4- methyl-3-pyridyl 214 ib(id). O S * 4 2-(iso-propylthio)-4- methyl-3-pyridyl 215 ib(id). O S * 5 2-(iso-propylthio)-4- methyl-3-pyridyl 216 ib(id). O S * 6 2-(iso-propylthio)-4- methyl-3-pyridyl 217 ib(id). O S * 7 2-(iso-propylthio)-4- methyl-3-pyridyl 218 ib(id). O S * 8 2-(iso-propylthio)-4- methyl-3-pyridyl 219 ib(id). O S * 9 2-(iso-propylthio)-4- methyl-3-pyridyl 220 ib(id). O S * 14 2-(iso-propylthio)-4- methyl-3-pyridyl *: Single Bond

TABLE 12 Compound No.

X Y Z n Het 221

S S * 1 2-(iso-propylthio)-4- methyl-3-pyridyl 222 ib(id). S S * 2 2-(iso-propylthio)-4- methyl-3-pyridyl 223 ib(id). S S * 3 2-(iso-propylthio)-4- methyl-3-pyridyl 224 ib(id). S S * 4 2-(iso-propylthio)-4- methyl-3-pyridyl 225 ib(id). S S * 5 2-(iso-propylthio)-4- methyl-3-pyridyl 226 ib(id). S S * 6 2-(iso-propylthio)-4- methyl-3-pyridyl 227 ib(id). S S * 7 2-(iso-propylthio)-4- methyl-3-pyridyl 228 ib(id). S S * 8 2-(iso-propylthio)-4- methyl-3-pyridyl 229 ib(id). S S * 9 2-(iso-propylthio)-4- methyl-3-pyridyl 230 ib(id). S S * 14 2-(iso-propylthio)-4- methyl-3-pyridyl 231 ib(id). NH S * 1 2-(iso-propylthio)-4- methyl-3-pyridyl 232 ib(id). NH S * 2 2-(iso-propylthio)-4- methyl-3-pyridyl 233 ib(id). NH S * 3 2-(iso-propylthio)-4- methyl-3-pyridyl 234 ib(id). NH S * 4 2-(iso-propylthio)-4- methyl-3-pyridyl 235 ib(id). NH S * 5 2-(iso-propylthio)-4- methyl-3-pyridyl 236 ib(id). NH S * 6 2-(iso-propylthio)-4- methyl-3-pyridyl 237 ib(id). NH S * 7 2-(iso-propylthio)-4- methyl-3-pyridyl 238 ib(id). NH S * 8 2-(iso-propylthio)-4- methyl-3-pyridyl 239 ib(id). NH S * 9 2-(iso-propylthio)-4- methyl-3-pyridyl 240 ib(id). NH S * 14 2-(iso-propylthio)-4- methyl-3-pyridyl *: Single Bond

TABLE 13 Com- pound No.

X Y Z n Het 241

O S * 1 2-methoxy-4-methyl-3- pyridyl 242 ib(id). O S * 2 2-methoxy-4-methyl-3- pyridyl 243 ib(id). O S * 3 2-methoxy-4-methyl-3- pyridyl 244 ib(id). O S * 4 2-methoxy-4-methyl-3- pyridyl 245 ib(id). O S * 5 2-methoxy-4-methyl-3- pyridyl 246 ib(id). O S * 6 2-methoxy-4-methyl-3- pyridyl 247 ib(id). O S * 7 2-methoxy-4-methyl-3- pyridyl 248 ib(id). O S * 8 2-methoxy-4-methyl-3- pyridyl 249 ib(id). O S * 9 2-methoxy-4-methyl-3- pyridyl 250 ib(id). O S * 14 2-methoxy-4-methyl-3- pyridyl 251 ib(id). S S * 1 2-methoxy-4-methyl-3- pyridyl 252 ib(id). S S * 2 2-methoxy-4-methyl-3- pyridyl 253 ib(id). S S * 3 2-methoxy-4-methyl-3- pyridyl 254 ib(id). S S * 4 2-methoxy-4-methyl-3- pyridyl 255 ib(id). S S * 5 2-methoxy-4-methyl-3- pyridyl 256 ib(id). S S * 6 2-methoxy-4-methyl-3- pyridyl 257 ib(id). S S * 7 2-methoxy-4-methyl-3- pyridyl 258 ib(id). S S * 8 2-methoxy-4-methyl-3- pyridyl 259 ib(id). S S * 9 2-methoxy-4-methyl-3- pyridyl 260 ib(id). S S * 14 2-methoxy-4-methyl-3- pyridyl *: Single Bond

TABLE 14 Com- pound No.

X Y Z n Het 261

NH S * 1 2-methoxy-4-methyl-3- pyridyl 262 ib(id). NH S * 2 2-methoxy-4-methyl-3- pyridyl 263 ib(id). NH S * 3 2-methoxy-4-methyl-3- pyridyl 264 ib(id). NH S * 4 2-methoxy-4-methyl-3- pyridyl 265 ib(id). NH S * 5 2-methoxy-4-methyl-3- pyridyl 266 ib(id). NH S * 6 2-methoxy-4-methyl-3- pyridyl 267 ib(id). NH S * 7 2-methoxy-4-methyl-3- pyridyl 268 ib(id). NH S * 8 2-methoxy-4-methyl-3- pyridyl 269 ib(id). NH S * 9 2-methoxy-4-methyl-3- pyridyl 270 ib(id). NH S * 14 2-methoxy-4-methyl-3- pyridyl 271 ib(id). O S * 1 2,6-bismethylthio-3- pyridyl 272 ib(id). O S * 2 2,6-bismethylthio-3- pyridyl 273 ib(id). O S * 3 2,6-bismethylthio-3- pyridyl 274 ib(id). O S * 4 2,6-bismethylthio-3- pyridyl 275 ib(id). O S * 5 2,6-bismethylthio-3- pyridyl 276 ib(id). O S * 6 2,6-bismethylthio-3- pyridyl 277 ib(id). O S * 7 2,6-bismethylthio-3- pyridyl 278 ib(id). O S * 8 2,6-bismethylthio-3- pyridyl 279 ib(id). O S * 9 2,6-bismethylthio-3- pyridyl 280 ib(id). O S * 14 2,6-bismethylthio-3- pyridyl *: Single Bond

TABLE 15 Compound No.

X Y Z n Het 281

S S * 1 2,6-bismethylthio-3- pyridyl 282 ib(id). S S * 2 2,6-bismethylthio-3- pyridyl 283 ib(id). S S * 3 2,6-bismethylthio-3- pyridyl 284 ib(id). S S * 4 2,6-bismethylthio-3- pyridyl 285 ib(id). S S * 5 2,6-bismethylthio-3- pyridyl 286 ib(id). S S * 6 2,6-bismethylthio-3- pyridyl 287 ib(id). S S * 7 2,6-bismethylthio-3- pyridyl 288 ib(id). S S * 8 2,6-bismethylthio-3- pyridyl 289 ib(id). S S * 9 2,6-bismethylthio-3- pyridyl 290 ib(id). S S * 14 2,6-bismethylthio-3- pyridyl 291 ib(id). NH S * 1 2,6-bismethylthio-3- pyridyl 292 ib(id). NH S * 2 2,6-bismethylthio-3- pyridyl 293 ib(id). NH S * 3 2,6-bismethylthio-3- pyridyl 294 ib(id). NH S * 4 2,6-bismethylthio-3- pyridyl 295 ib(id). NH S * 5 2,6-bismethylthio-3- pyridyl 296 ib(id). NH S * 6 2,6-bismethylthio-3- pyridyl 297 ib(id). NH S * 7 2,6-bismethylthio-3- pyridyl 298 ib(id). NH S * 8 2,6-bismethylthio-3- pyridyl 299 ib(id). NH S * 9 2,6-bismethylthio-3- pyridyl 300 ib(id). NH S * 14 2,6-bismethylthio-3- pyridyl *: Single Bond

TABLE 16 Com- pound No.

X Y Z n Het 301

O S * 1 2,6-bisethylthio-3-pyridyl 302 ib(id). O S * 2 2,6-bisethylthio-3-pyridyl 303 ib(id). O S * 3 2,6-bisethylthio-3-pyridyl 304 ib(id). O S * 4 2,6-bisethylthio-3-pyridyl 305 ib(id). O S * 5 2,6-bisethylthio-3-pyridyl 306 ib(id). O S * 6 2,6-bisethylthio-3-pyridyl 307 ib(id). O S * 7 2,6-bisethylthio-3-pyridyl 308 ib(id). O S * 8 2,6-bisethylthio-3-pyridyl 309 ib(id). O S * 9 2,6-bisethylthio-3-pyridyl 310 ib(id). O S * 14 2,6-bisethylthio-3-pyridyl 311 ib(id). S S * 1 2,6-bisethylthio-3-pyridyl 312 ib(id). S S * 2 2,6-bisethylthio-3-pyridyl 313 ib(id). S S * 3 2,6-bisethylthio-3-pyridyl 314 ib(id). S S * 4 2,6-bisethylthio-3-pyridyl 315 ib(id). S S * 5 2,6-bisethylthio-3-pyridyl 316 ib(id). S S * 6 2,6-bisethylthio-3-pyridyl 317 ib(id). S S * 7 2,6-bisethylthio-3-pyridyl 318 ib(id). S S * 8 2,6-bisethylthio-3-pyridyl 319 ib(id). S S * 9 2,6-bisethylthio-3-pyridyl 320 ib(id). S S * 14 2,6-bisethylthio-3-pyridyl *: Single Bond

TABLE 17 Com- pound No.

X Y Z n Het 321

NH S * 1 2,6-bisethylthio-3-pyridyl 322 ib(id). NH S * 2 2,6-bisethylthio-3-pyridyl 323 ib(id). NH S * 3 2,6-bisethylthio-3-pyridyl 324 ib(id). NH S * 4 2,6-bisethylthio-3-pyridyl 325 ib(id). NH S * 5 2,6-bisethylthio-3-pyridyl 326 ib(id). NH S * 6 2,6-bisethylthio-3-pyridyl 327 ib(id). NH S * 7 2,6-bisethylthio-3-pyridyl 328 ib(id). NH S * 8 2,6-bisethylthio-3-pyridyl 329 ib(id). NH S * 9 2,6-bisethylthio-3-pyridyl 330 ib(id). NH S * 14 2,6-bisethylthio-3-pyridyl 331 ib(id). O S * 1 2,6-bis(iso-propylthio)-3- pyridyl 332 ib(id). O S * 2 2,6-bis(iso-propylthio)-3- pyridyl 333 ib(id). O S * 3 2,6-bis(iso-propylthio)-3- pyridyl 334 ib(id). O S * 4 2,6-bis(iso-propylthio)-3- pyridyl 335 ib(id). O S * 5 2,6-bis(iso-propylthio)-3- pyridyl 336 ib(id). O S * 6 2,6-bis(iso-propylthio)-3- pyridyl 337 ib(id). O S * 7 2,6-bis(iso-propylthio)-3- pyridyl 338 ib(id). O S * 8 2,6-bis(iso-propylthio)-3- pyridyl 339 ib(id). O S * 9 2,6-bis(iso-propylthio)-3- pyridyl 340 ib(id). O S * 14 2,6-bis(iso-propylthio)-3- pyridyl *: Single Bond

TABLE 18 Com- pound No.

X Y Z n Het 341

S S * 1 2,6-bis(isopropylthio)-3- pyridyl 342 ib(id). S S * 2 2,6-bis(isopropylthio)-3- pyridyl 343 ib(id). S S * 3 2,6-bis(isopropylthio)-3- pyridyl 344 ib(id). S S * 4 2,6-bis(isopropylthio)-3- pyridyl 345 ib(id). S S * 5 2,6-bis(isopropylthio)-3- pyridyl 346 ib(id). S S * 6 2,6-bis(isopropylthio)-3- pyridyl 347 ib(id). S S * 7 2,6-bis(isopropylthio)-3- pyridyl 348 ib(id). S S * 8 2,6-bis(isopropylthio)-3- pyridyl 349 ib(id). S S * 9 2,6-bis(isopropylthio)-3- pyridyl 350 ib(id). S S * 14 2,6-bis(isopropylthio)-3- pyridyl 351 ib(id). NH S * 1 2,6-bis(isopropylthio)-3- pyridyl 352 ib(id). NH S * 2 2,6-bis(isopropylthio)-3- pyridyl 353 ib(id). NH S * 3 2,6-bis(isopropylthio)-3- pyridyl 354 ib(id). NH S * 4 2,6-bis(isopropylthio)-3- pyridyl 355 ib(id). NH S * 5 2,6-bis(isopropylthio)-3- pyridyl 356 ib(id). NH S * 6 2,6-bis(isopropylthio)-3- pyridyl 357 ib(id). NH S * 7 2,6-bis(isopropylthio)-3- pyridyl 358 ib(id). NH S * 8 2,6-bis(isopropylthio)-3- pyridyl 359 ib(id). NH S * 9 2,6-bis(isopropylthio)-3- pyridyl 360 ib(id). NH S * 14 2,6-bis(isopropylthio)-3- pyridyl *: Single Bond

TABLE 19 Com- pound No.

X Y Z n Het 361

O S * 1 2-methylthio-6-methoxy-3- pyridyl 362 ib(id). O S * 2 2-methylthio-6-methoxy-3- pyridyl 363 ib(id). O S * 3 2-methylthio-6-methoxy-3- pyridyl 364 ib(id). O S * 4 2-methylthio-6-methoxy-3- pyridyl 365 ib(id). O S * 5 2-methylthio-6-methoxy-3- pyridyl 366 ib(id). O S * 6 2-methylthio-6-methoxy-3- pyridyl 367 ib(id). O S * 7 2-methylthio-6-methoxy-3- pyridyl 368 ib(id). O S * 8 2-methylthio-6-methoxy-3- pyridyl 369 ib(id). O S * 9 2-methylthio-6-methoxy-3- pyridyl 370 ib(id). O S * 14 2-methylthio-6-methoxy-3- pyridyl 371 ib(id). S S * 1 2-methylthio-6-methoxy-3- pyridyl 372 ib(id). S S * 2 2-methylthio-6-methoxy-3- pyridyl 373 ib(id). S S * 3 2-methylthio-6-methoxy-3- pyridyl 374 ib(id). S S * 4 2-methylthio-6-methoxy-3- pyridyl 375 ib(id). S S * 5 2-methylthio-6-methoxy-3- pyridyl 376 ib(id). S S * 6 2-methylthio-6-methoxy-3- pyridyl 377 ib(id). S S * 7 2-methylthio-6-methoxy-3- pyridyl 378 ib(id). S S * 5 2-methylthio-6-methoxy-3- pyridyl 379 ib(id). S S * 9 2-methylthio-6-methoxy-3- pyridyl 380 ib(id). S S * 14 2-methylthio-6-methoxy-3- pyridyl *: Single Bond

TABLE 20 Com- pound No.

X Y Z n Het 381

NH S * 1 2-methylthio-6-methoxy- 3-pyridyl 382 ib(id). NH S * 2 2-methylthio-6-methoxy- 3-pyridyl 383 ib(id). NH S * 3 2-methylthio-6-methoxy- 3-pyridyl 384 ib(id). NH S * 4 2-methylthio-6-methoxy- 3-pyridyl 385 ib(id). NH S * 5 2-methylthio-6-methoxy- 3-pyridyl 386 ib(id). NH S * 6 2-methylthio-6-methoxy- 3-pyridyl 387 ib(id). NH S * 7 2-methylthio-6-methoxy- 3-pyridyl 388 ib(id). NH S * 8 2-methylthio-6-methoxy- 3-pyridyl 389 ib(id). NH S * 9 2-methylthio-6-methoxy- 3-pyridyl 390 ib(id). NH S * 14 2-methylthio-6-methoxy- 3-pyridyl 391 ib(id). O S * 1 2-ethylthio-6-methoxy-3- pyridyl 392 ib(id). O S * 2 2-ethylthio-6-methoxy-3- pyridyl 393 ib(id). O S * 3 2-ethylthio-6-methoxy-3- pyridyl 394 ib(id). O S * 4 2-ethylthio-6-methoxy-3- pyridyl 395 ib(id). O S * 5 2-ethylthio-6-methoxy-3- pyridyl 396 ib(id). O S * 6 2-ethylthio-6-methoxy-3- pyridyl 397 ib(id). O S * 7 2-ethylthio-6-methoxy-3- pyridyl 398 ib(id). O S * 8 2-ethylthio-6-methoxy-3- pyridyl 399 ib(id). O S * 9 2-ethylthio-6-methoxy-3- pyridyl 400 ib(id). O S * 14 2-ethylthio-6-methoxy-3- pyridyl *: Single Bond

TABLE 21 Compound No.

X Y Z n Het 401

S S * 1 2-ethylthio-6-methoxy-3-pyridyl 402 ib(id). S S * 2 2-ethylthio-6-methoxy-3-pyridyl 403 ib(id). S S * 3 2-ethylthio-6-methoxy-3-pyridyl 404 ib(id). S S * 4 2-ethylthio-6-methoxy-3-pyridyl 405 ib(id). S S * 5 2-ethylthio-6-methoxy-3-pyridyl 406 ib(id). S S * 6 2-ethylthio-6-methoxy-3-pyridyl 407 ib(id). S S * 7 2-ethylthio-6-methoxy-3-pyridyl 408 ib(id). S S * 8 2-ethylthio-6-methoxy-3-pyridyl 409 ib(id). S S * 9 2-ethylthio-6-methoxy-3-pyridyl 410 ib(id). S S * 14 2-ethylthio-6-methoxy-3-pyridyl 411 ib(id). NH S * 1 2-ethylthio-6-methoxy-3-pyridyl 412 ib(id). NH S * 2 2-ethylthio-6-methoxy-3-pyridyl 413 ib(id). NH S * 3 2-ethylthio-6-methoxy-3-pyridyl 414 ib(id). NH S * 4 2-ethylthio-6-methoxy-3-pyridyl 415 ib(id). NH S * 5 2-ethylthio-6-methoxy-3-pyridyl 416 ib(id). NH S * 6 2-ethylthio-6-methoxy-3-pyridyl 417 ib(id). NH S * 7 2-ethylthio-6-methoxy-3-pyridyl 418 ib(id). NH S * 8 2-ethylthio-6-methoxy-3-pyridyl 419 ib(id). NH S * 9 2-ethylthio-6-methoxy-3-pyridyl 420 ib(id). NH S * 14 2-ethylthio-6-methoxy-3-pyridyl *: Single Bond

TABLE 22 Compound No.

X Y Z n Het 421

O S * 1 2-(iso-propylthio)-6-methoxy-3-pyridyl 422 ib(id). O S * 2 2-(iso-propylthio)-6-methoxy-3-pyridyl 423 ib(id). O S * 3 2-(iso-propylthio)-6-methoxy-3-pyridyl 424 ib(id). O S * 4 2-(iso-propylthio)-6-methoxy-3-pyridyl 425 ib(id). O S * 5 2-(iso-propylthio)-6-methoxy-3-pyridyl 426 ib(id). O S * 6 2-(iso-propylthio)-6-methoxy-3-pyridyl 427 ib(id). O S * 7 2-(iso-propylthio)-6-methoxy-3-pyridyl 428 ib(id). O S * 8 2-(iso-propylthio)-6-methoxy-3-pyridyl 429 ib(id). O S * 9 2-(iso-propylthio)-6-methoxy-3-pyridyl 430 ib(id). O S * 14 2-(iso-propylthio)-6-methoxy-3-pyridyl 431 ib(id). S S * 1 2-(iso-propylthio)-6-methoxy-3-pyridyl 432 ib(id). S S * 2 2-(iso-propylthio)-6-methoxy-3-pyridyl 433 ib(id). S S * 3 2-(iso-propylthio)-6-methoxy-3-pyridyl 434 ib(id). S S * 4 2-(iso-propylthio)-6-methoxy-3-pyridyl 435 ib(id). S S * 5 2-(iso-propylthio)-6-methoxy-3-pyridyl 436 ib(id). S S * 6 2-(iso-propylthio)-6-methoxy-3-pyridyl 437 ib(id). S S * 7 2-(iso-propylthio)-6-methoxy-3-pyridyl 438 ib(id). S S * 8 2-(iso-propylthio)-6-methoxy-3-pyridyl 439 ib(id). S S * 9 2-(iso-propylthio)-6-methoxy-3-pyridyl 440 ib(id). S S * 14 2-(iso-propylthio)-6-methoxy-3-pyridyl *: Single Bond

TABLE 23 Compound No.

X Y Z n Het 441

NH S * 1 2-(iso-propylthio)-6-methoxy-3-pyridyl 442 ib(id). NH S * 2 2-(iso-propylthio)-6-methoxy-3-pyridyl 443 ib(id). NH S * 3 2-(iso-propylthio)-6-methoxy-3-pyridyl 444 ib(id). NH S * 4 2-(iso-propylthio)-6-methoxy-3-pyridyl 445 ib(id). NH S * 5 2-(iso-propylthio)-6-methoxy-3-pyridyl 446 ib(id). NH S * 6 2-(iso-propylthio)-6-methoxy-3-pyridyl 447 ib(id). NH S * 7 2-(iso-propylthio)-6-methoxy-3-pyridyl 448 ib(id). NH S * 8 2-(iso-propylthio)-6-methoxy-3-pyridyl 449 ib(id). NH S * 9 2-(iso-propylthio)-6-methoxy-3-pyridyl 450 ib(id). NH S * 14 2-(iso-propylthio)-6-methoxy-3-pyridyl 451 ib(id). O S * 1 2-methylthio-6-methyl-3-pyridyl 452 ib(id). O S * 2 2-methylthio-6-methyl-3-pyridyl 453 ib(id). O S * 3 2-methylthio-6-methyl-3-pyridyl 454 ib(id). O S * 4 2-methylthio-6-methyl-3-pyridyl 455 ib(id). O S * 5 2-methylthio-6-methyl-3-pyridyl 456 ib(id). O S * 6 2-methylthio-6-methyl-3-pyridyl 457 ib(id). O S * 7 2-methylthio-6-methyl-3-pyridyl 458 ib(id). O S * 8 2-methylthio-6-methyl-3-pyridyl 459 ib(id). O S * 9 2-methylthio-6-methyl-3-pyridyl 460 ib(id). O S * 14 2-methylthio-6-methyl-3-pyridyl *: Single Bond

TABLE 24 Compound No.

X Y Z n Het 461

S S * 1 2-methylthio-6-methyl-3-pyridyl 462 ib(id). S S * 2 2-methylthio-6-methyl-3-pyridyl 463 ib(id). S S * 3 2-methylthio-6-methyl-3-pyridyl 464 ib(id). S S * 4 2-methylthio-6-methyl-3-pyridyl 465 ib(id). S S * 5 2-methylthio-6-methyl-3-pyridyl 466 ib(id). S S * 6 2-methylthio-6-methyl-3-pyridyl 467 ib(id). S S * 7 2-methylthio-6-methyl-3-pyridyl 468 ib(id). S S * 8 2-methylthio-6-methyl-3-pyridyl 469 ib(id). S S * 9 2-methylthio-6-methyl-3-pyridyl 470 ib(id). S S * 14 2-methylthio-6-methyl-3-pyridyl 471 ib(id). NH S * 1 2-methylthio-6-methyl-3-pyridyl 472 ib(id). NH S * 2 2-methylthio-6-methyl-3-pyridyl 473 ib(id). NH S * 3 2-methylthio-6-methyl-3-pyridyl 474 ib(id). NH S * 4 2-methylthio-6-methyl-3-pyridyl 475 ib(id). NH S * 5 2-methylthio-6-methyl-3-pyridyl 476 ib(id). NH S * 6 2-methylthio-6-methyl-3-pyridyl 477 ib(id). NH S * 7 2-methylthio-6-methyl-3-pyridyl 478 ib(id). NH S * 8 2-methylthio-6-methyl-3-pyridyl 479 ib(id). NH S * 9 2-methylthio-6-methyl-3-pyridyl 480 ib(id). NH S * 14 2-methylthio-6-methyl-3-pyridyl *: Single Bond

TABLE 25 Compound No.

X Y Z n Het 481

O S * 1 2-ethylthio-6-methyl-3-pyridyl 482 ib(id). O S * 2 2-ethylthio-6-methyl-3-pyridyl 483 ib(id). O S * 3 2-ethylthio-6-methyl-3-pyridyl 484 ib(id). O S * 4 2-ethylthio-6-methyl-3-pyridyl 485 ib(id). O S * 5 2-ethylthio-6-methyl-3-pyridyl 486 ib(id). O S * 6 2-ethylthio-6-methyl-3-pyridyl 487 ib(id). O S * 7 2-ethylthio-6-methyl-3-pyridyl 488 ib(id). O S * 8 2-ethylthio-6-methyl-3-pyridyl 489 ib(id). O S * 9 2-ethylthio-6-methyl-3-pyridyl 490 ib(id). O S * 14 2-ethylthio-6-methyl-3-pyridyl 491 ib(id). S S * 1 2-ethylthio-6-methyl-3-pyridyl 492 ib(id). S S * 2 2-ethylthio-6-methyl-3-pyridyl 493 ib(id). S S * 3 2-ethylthio-6-methyl-3-pyridyl 494 ib(id). S S * 4 2-ethylthio-6-methyl-3-pyridyl 495 ib(id). S S * 5 2-ethylthio-6-methyl-3-pyridyl 496 ib(id). S S * 6 2-ethylthio-6-methyl-3-pyridyl 497 ib(id). S S * 7 2-ethylthio-6-methyl-3-pyridyl 498 ib(id). S S * 8 2-ethylthio-6-methyl-3-pyridyl 499 ib(id). S S * 9 2-ethylthio-6-methyl-3-pyridyl 500 ib(id). S S * 14 2-ethylthio-6-methyl-3-pyridyl *: Single Bond

TABLE 26 Compound No.

X Y Z n Het 501

NH S * 1 2-ethylthio-6-methyl-3-pyridyl 502 ib(id). NH S * 2 2-ethylthio-6-methyl-3-pyridyl 503 ib(id). NH S * 3 2-ethylthio-6-methyl-3-pyridyl 504 ib(id). NH S * 4 2-ethylthio-6-methyl-3-pyridyl 505 ib(id). NH S * 5 2-ethylthio-6-methyl-3-pyridyl 506 ib(id). NH S * 6 2-ethylthio-6-methyl-3-pyridyl 507 ib(id). NH S * 7 2-ethylthio-6-methyl-3-pyridyl 508 ib(id). NH S * 8 2-ethylthio-6-methyl-3-pyridyl 509 ib(id). NH S * 9 2-ethylthio-6-methyl-3-pyridyl 510 ib(id). NH S * 14 2-ethylthio-6-methyl-3-pyridyl 511 ib(id). O S * 1 2-(iso-propylthio)-6-methyl-3-pyridyl 512 ib(id). O S * 2 2-(iso-propylthio)-6-methyl-3-pyridyl 513 ib(id). O S * 3 2-(iso-propylthio)-6-methyl-3-pyridyl 514 ib(id). O S * 4 2-(iso-propylthio)-6-methyl-3-pyridyl 515 ib(id). O S * 5 2-(iso-propylthio)-6-methyl-3-pyridyl 516 ib(id). O S * 6 2-(iso-propylthio)-6-methyl-3-pyridyl 517 ib(id). O S * 7 2-(iso-propylthio)-6-methyl-3-pyridyl 518 ib(id). O S * 8 2-(iso-propylthio)-6-methyl-3-pyridyl 519 ib(id). O S * 9 2-(iso-propylthio)-6-methyl-3-pyridyl 520 ib(id). O S * 14 2-(iso-propylthio)-6-methyl-3-pyridyl *: Single Bond

TABLE 27 Compound No.

X Y Z n Het 521

S S * 1 2-(iso-propylthio)-6-methyl-3-pyridyl 522 ib(id). S S * 2 2-(iso-propylthio)-6-methyl-3-pyridyl 523 ib(id). S S * 3 2-(iso-propylthio)-6-methyl-3-pyridyl 524 ib(id). S S * 4 2-(iso-propylthio)-6-methyl-3-pyridyl 525 ib(id). S S * 5 2-(iso-propylthio)-6-methyl-3-pyridyl 526 ib(id). S S * 6 2-(iso-propylthio)-6-methyl-3-pyridyl 527 ib(id). S S * 7 2-(iso-propylthio)-6-methyl-3-pyridyl 528 ib(id). S S * 8 2-(iso-propylthio)-6-methyl-3-pyridyl 529 ib(id). S S * 9 2-(iso-propylthio)-6-methyl-3-pyridyl 530 ib(id). S S * 14 2-(iso-propylthio)-6-methyl-3-pyridyl 531 ib(id). NH S * 1 2-(iso-propylthio)-6-methyl-3-pyridyl 532 ib(id). NH S * 2 2-(iso-propylthio)-6-methyl-3-pyridyl 533 ib(id). NH S * 3 2-(iso-propylthio)-6-methyl-3-pyridyl 534 ib(id). NH S * 4 2-(iso-propylthio)-6-methyl-3-pyridyl 535 ib(id). NH S * 5 2-(iso-propylthio)-6-methyl-3-pyridyl 536 ib(id). NH S * 6 2-(iso-propylthio)-6-methyl-3-pyridyl 537 ib(id). NH S * 7 2-(iso-propylthio)-6-methyl-3-pyridyl 538 ib(id). NH S * 8 2-(iso-propylthio)-6-methyl-3-pyridyl 539 ib(id). NH S * 9 2-(iso-propylthio)-6-methyl-3-pyridyl 540 ib(id). NH S * 14 2-(iso-propylthio)-6-methyl-3-pyridyl *: Single Bond

TABLE 28 Compound No.

X Y Z n Het 541

O S * 1 2,6-dimethoxyl-3-pyridyl 542 ib(id). O S * 2 2,6-dimethoxyl-3-pyridyl 543 ib(id). O S * 3 2,6-dimethoxyl-3-pyridyl 544 ib(id). O S * 4 2,6-dimethoxyl-3-pyridyl 545 ib(id). O S * 5 2,6-dimethoxyl-3-pyridyl 546 ib(id). O S * 6 2,6-dimethoxyl-3-pyridyl 547 ib(id). O S * 7 2,6-dimethoxyl-3-pyridyl 548 ib(id). O S * 8 2,6-dimethoxyl-3-pyridyl 549 ib(id). O S * 9 2,6-dimethoxyl-3-pyridyl 550 ib(id). O S * 14 2,6-dimethoxyl-3-pyridyl 551 ib(id). S S * 1 2,6-dimethoxyl-3-pyridyl 552 ib(id). S S * 2 2,6-dimethoxyl-3-pyridyl 553 ib(id). S S * 3 2,6-dimethoxyl-3-pyridyl 554 ib(id). S S * 4 2,6-dimethoxyl-3-pyridyl 555 ib(id). S S * 5 2,6-dimethoxyl-3-pyridyl 556 ib(id). S S * 6 2,6-dimethoxyl-3-pyridyl 557 ib(id). S S * 7 2,6-dimethoxyl-3-pyridyl 558 ib(id). S S * 8 2,6-dimethoxyl-3-pyridyl 559 ib(id). S S * 9 2,6-dimethoxyl-3-pyridyl 560 ib(id). S S * 14 2,6-dimethoxyl-3-pyridyl *: Single Bond

TABLE 29 Compound No.

X Y Z n Het 561

NH S * 1 2,6-dimethoxyl-3-pyridyl 562 ib(id). NH S * 2 2,6-dimethoxyl-3-pyridyl 563 ib(id). NH S * 3 2,6-dimethoxyl-3-pyridyl 564 ib(id). NH S * 4 2,6-dimethoxyl-3-pyridyl 565 ib(id). NH S * 5 2,6-dimethoxyl-3-pyridyl 566 ib(id). NH S * 6 2,6-dimethoxyl-3-pyridyl 567 ib(id). NH S * 7 2,6-dimethoxyl-3-pyridyl 568 ib(id). NH S * 8 2,6-dimethoxyl-3-pyridyl 569 ib(id). NH S * 9 2,6-dimethoxyl-3-pyridyl 570 ib(id). NH S * 14 2,6-dimethoxyl-3-pyridyl 571 ib(id). O S * 1 2-methoxy-6-methyl-3-pyridyl 572 ib(id). O S * 2 2-methoxy-6-methyl-3-pyridyl 573 ib(id). O S * 3 2-methoxy-6-methyl-3-pyridyl 574 ib(id). O S * 4 2-methoxy-6-methyl-3-pyridyl 575 ib(id). O S * 5 2-methoxy-6-methyl-3-pyridyl 576 ib(id). O S * 6 2-methoxy-6-methyl-3-pyridyl 577 ib(id). O S * 7 2-methoxy-6-methyl-3-pyridyl 578 ib(id). O S * 8 2-methoxy-6-methyl-3-pyridyl 579 ib(id). O S * 9 2-methoxy-6-methyl-3-pyridyl 580 ib(id). O S * 14 2-methoxy-6-methyl-3-pyridyl *: Single Bond

TABLE 30 Compound No.

X Y Z n Het 581

S S * 1 2-methoxy-6-methyl-3-pyridyl 582 ib(id). S S * 2 2-methoxy-6-methyl-3-pyridyl 583 ib(id). S S * 3 2-methoxy-6-methyl-3-pyridyl 584 ib(id). S S * 4 2-methoxy-6-methyl-3-pyridyl 585 ib(id). S S * 5 2-methoxy-6-methyl-3-pyridyl 586 ib(id). S S * 6 2-methoxy-6-methyl-3-pyridyl 587 ib(id). S S * 7 2-methoxy-6-methyl-3-pyridyl 588 ib(id). S S * 8 2-methoxy-6-methyl-3-pyridyl 589 ib(id). S S * 9 2-methoxy-6-methyl-3-pyridyl 590 ib(id). S S * 14 2-methoxy-6-methyl-3-pyridyl 591 ib(id). NH S * 1 2-methoxy-6-methyl-3-pyridyl 592 ib(id). NH S * 2 2-methoxy-6-methyl-3-pyridyl 593 ib(id). NH S * 3 2-methoxy-6-methyl-3-pyridyl 594 ib(id). NH S * 4 2-methoxy-6-methyl-3-pyridyl 595 ib(id). NH S * 5 2-methoxy-6-methyl-3-pyridyl 596 ib(id). NH S * 6 2-methoxy-6-methyl-3-pyridyl 597 ib(id). NH S * 7 2-methoxy-6-methyl-3-pyridyl 598 ib(id). NH S * 8 2-methoxy-6-methyl-3-pyridyl 599 ib(id). NH S * 9 2-methoxy-6-methyl-3-pyridyl 600 ib(id). NH S * 14 2-methoxy-6-methyl-3-pyridyl *: Single Bond

TABLE 31 Com- pound No.

X Y Z n Het 601

O S * 1 2-methyl-6-methythio-3- pyridyl 602 ″ O S * 2 2-methyl-6-methythio-3- pyridyl 603 ″ O S * 3 2-methyl-6-methythio-3- pyridyl 604 ″ O S * 4 2-methyl-6-methythio-3- pyridyl 605 ″ O S * 5 2-methyl-6-methythio-3- pyridyl 606 ″ O S * 6 2-methyl-6-methythio-3- pyridyl 607 ″ O S * 7 2-methyl-6-methythio-3- pyridyl 608 ″ O S * 8 2-methyl-6-methythio-3- pyridyl 609 ″ O S * 9 2-methyl-6-methythio-3- pyridyl 610 ″ O S * 14  2-methyl-6-methythio-3- pyridyl 611 ″ S S * 1 2-methyl-6-methythio-3- pyridyl 612 ″ S S * 2 2-methyl-6-methythio-3- pyridyl 613 ″ S S * 3 2-methyl-6-methythio-3- pyridyl 614 ″ S S * 4 2-methyl-6-methythio-3- pyridyl 615 ″ S S * 5 2-methyl-6-methythio-3- pyridyl 616 ″ S S * 6 2-methyl-6-methythio-3- pyridyl 617 ″ S S * 7 2-methyl-6-methythio-3- pyridyl 618 ″ S S * 8 2-methyl-6-methythio-3- pyridyl 619 ″ S S * 9 2-methyl-6-methythio-3- pyridyl 620 ″ S S * 14 2-methyl-6-methythio-3- pyridyl * Single Bond

TABLE 32 Com- pound No.

X Y Z n Het 621

NH S * 1 2-methyl-6-methythio- 3-pyridyl 622 ″ NH S * 2 2-methyl-6-methythio- 3-pyridyl 623 ″ NH S * 3 2-methyl-6-methythio- 3-pyridyl 624 ″ NH S * 4 2-methyl-6-methythio- 3-pyridyl 625 ″ NH S * 5 2-methyl-6-methythio- 3-pyridyl 626 ″ NH S * 6 2-methyl-6-methythio- 3-pyridyl 627 ″ NH S * 7 2-methyl-6-methythio- 3-pyridyl 628 ″ NH S * 8 2-methyl-6-methythio- 3-pyridyl 629 ″ NH S * 9 2-methyl-6-methythio- 3-pyridyl 630 ″ NH S * 14  2-methyl-6-methythio- 3-pyridyl 631 ″ O S * 1 2-methyl-6-ethythio-3- pyridyl 632 ″ O S * 2 2-methyl-6-ethythio-3- pyridyl 633 ″ O S * 3 2-methyl-6-ethythio-3- pyridyl 634 ″ O S * 4 2-methyl-6-ethythio-3- pyridyl 635 ″ O S * 5 2-methyl-6-ethythio-3- pyridyl 636 ″ O S * 6 2-methyl-6-ethythio-3- pyridyl 637 ″ O S * 7 2-methyl-6-ethythio-3- pyridyl 638 ″ O S * 8 2-methyl-6-ethythio-3- pyridyl 639 ″ O S * 9 2-methyl-6-ethythio-3- pyridyl 640 ″ O S * 14  2-methyl-6-ethythio-3- pyridyl * Single Bond

TABLE 33 Com- pound No.

X Y Z n Het 641

S S * 1 2-methyl-6-ethythio- 3-pyridyl 642 ″ S S * 2 2-methyi-6-ethythio- 3-pyridyl 643 ″ S S * 3 2-methyl-6-ethythio- 3-pyridyl 644 ″ S S * 4 2-methyl-6-ethythio- 3-pyridyl 645 ″ S S * 5 2-methyl-6-ethythio- 3-pyridyl 646 ″ S S * 6 2-methyl-6-ethythio- 3-pyridyl 647 ″ S S * 7 2-methyl-6-ethythio- 3-pyridyl 648 ″ S S * 8 2-methyl-6-ethythio- 3-pyridyl 649 ″ S S * 9 2-methyl-6-ethythio- 3-pyridyl 650 ″ S S * 14  2-methyl-6-ethythio- 3-pyridyl 651 ″ NH S * 1 2-methyl-6-ethythio- 3-pyridyl 652 ″ NH S * 2 2-methyl-6-ethythio- 3-pyridyl 653 ″ NH S * 3 2-methyl-6-ethythio- 3-pyridyl 654 ″ NH S * 4 2-methyl-6-ethythio- 3-pyridyl 655 ″ NH S * 5 2-methyl-6-ethythio- 3-pyridyl 656 ″ NH S * 6 2-methyl-6-ethythio- 3-pyridyl 657 ″ NH S * 7 2-methyl-6-ethythio- 3-pyridyl 658 ″ NH S * 8 2-methyl-6-ethythio- 3-pyridyl 659 ″ NH S * 9 2-methyl-6-ethythio- 3-pyridyl 660 ″ NH S * 14  2-methyl-6-ethythio- 3-pyridyl * Single Bond

TABLE 34 Com- pound No.

X Y Z n Het 661

O S * 1 2-methyl-6-(iso- propylthio)-3-pyridyl 662 ″ O S * 2 2-methyl-6-(iso- propylthio)-3-pyridyl 663 ″ O S * 3 2-methyl-6-(iso- propylthio)-3-pyridyl 664 ″ O S * 4 2-methyl-6-(iso- propylthio)-3-pyridyl 665 ″ O S * 5 2-methyl-6-(iso- propylthio)-3-pyridyl 666 ″ O S * 6 2-methyl-6-(iso- propylthio)-3-pyridyl 667 ″ O S * 7 2-methyl-6-(iso- propylthio)-3-pyridyl 668 ″ O S * 8 2-methyl-6-(iso- propylthio)-3-pyridyl 669 ″ O S * 9 2-methyl-6-(iso- propylthio)-3-pyridyl 670 ″ O S * 14  2-methyl-6-(iso- propylthio)-3-pyridyl 671 ″ S S * 1 2-methyl-6-(iso- propylthio)-3-pyridyl 672 ″ S S * 2 2-methyl-6-(iso- propylthio)-3-pyridyl 673 ″ S S * 3 2-methyl-6-(iso- propylthio)-3-pyridyl 674 ″ S S * 4 2-methyl-6-(iso- propylthio)-3-pyridyl 675 ″ S S * 5 2-methyl-6-(iso- propylthio)-3-pyridyl 676 ″ S S * 6 2-methyl-6-(iso- propylthio)-3-pyridyl 677 ″ S S * 7 2-methyl-6-(iso- propylthio)-3-pyridyl 678 ″ S S * 8 2-methyl-6-(iso- propylthio)-3-pyridyl 679 ″ S S * 9 2-methyl-6-(iso- propylthio)-3-pyridyl 680 ″ S S * 14  2-methyl-6-(iso- propylthio)-3-pyridyl * Single Bond

TABLE 35 Com- pound No.

X Y Z n Het 681

NH S * 1 2-methyl-6-(iso-propylthio)-3-pyridyl 682 ″ NH S * 2 2-methyl-6-(iso-propylthio)-3-pyridyl 683 ″ NH S * 3 2-methyl-6-(iso-propylthio)-3-pyridyl 684 ″ NH S * 4 2-methyl-6-(iso-propylthio)-3-pyridyl 685 ″ NH S * 5 2-methyl-6-(iso-propylthio)-3-pyridyl 686 ″ NH S * 6 2-methyl-6-(iso-propylthio)-3-pyridyl 687 ″ NH S * 7 2-methyl-6-(iso-propylthio)-3-pyridyl 688 ″ NH S * 8 2-methyl-6-(iso-propylthio)-3-pyridyl 689 ″ NH S * 9 2-methyl-6-(iso-propylthio)-3-pyridyl 690 ″ NH S * 14  2-methyl-6-(iso-propylthio)-3-pyridyl 691 ″ O S * 1 2-methyl-6-mehoxy-3-pyridyl 692 ″ O S * 2 2-methyl-6-mehoxy-3-pyridyl 693 ″ O S * 3 2-methyl-6-mehoxy-3-pyridyl 694 ″ O S * 4 2-methyl-6-mehoxy-3-pyridyl 695 ″ O S * 5 2-methyl-6-mehoxy-3-pyridyl 696 ″ O S * 6 2-methyl-6-mehoxy-3-pyridyl 697 ″ O S * 7 2-methyl-6-mehoxy-3-pyridyl 698 ″ O S * 8 2-methyl-6-mehoxy-3-pyridyl 699 ″ O S * 9 2-methyl-6-mehoxy-3-pyridyl 700 ″ O S * 14  2-methyl-6-mehoxy-3-pyridyl * Single Bond

TABLE 36 Com- pound No.

X Y Z n Het 701

S S * 1 2-methyl-6-mehoxy-3- pyridyl 702 ″ S S * 2 2-methyl-6-mehoxy-3- pyridyl 703 ″ S S * 3 2-methyl-6-mehoxy-3- pyridyl 704 ″ S S * 4 2-methyl-6-mehoxy-3- pyridyl 705 ″ S S * 5 2-methyl-6-mehoxy-3- pyridyl 706 ″ S S * 6 2-methyl-6-mehoxy-3- pyridyl 707 ″ S S * 7 2-methyl-6-mehoxy-3- pyridyl 708 ″ S S * 8 2-methyl-6-mehoxy-3- pyridyl 709 ″ S S * 9 2-methyl-6-mehoxy-3- pyridyl 710 ″ S S * 14  2-methyl-6-mehoxy-3- pyridyl 711 ″ NH S * 1 2-methyl-6-mehoxy-3- pyridyl 712 ″ NH S * 2 2-methyl-6-mehoxy-3- pyridyl 713 ″ NH S * 3 2-methyl-6-mehoxy-3- pyridyl 714 ″ NH S * 4 2-methyl-6-mehoxy-3- pyridyl 715 ″ NH S * 5 2-methyl-6-mehoxy-3- pyridyl 716 ″ NH S * 6 2-methyl-6-mehoxy-3- pyridyl 717 ″ NH S * 7 2-methyl-6-mehoxy-3- pyridyl 718 ″ NH S * 8 2-methyl-6-mehoxy-3- pyridyl 719 ″ NH S * 9 2-methyl-6-mehoxy-3- pyridyl 720 ″ NH S * 14  2-methyl-6-mehoxy-3- pyridyl * Single Bond

TABLE 37 Com- pound No.

X Y Z n Het 721

O S * 1 2, 6-dimethyl-3-pyridyl 722 ″ O S * 2 2, 6-dimethyl-3-pyridyl 723 ″ O S * 3 2, 6-dimethyl-3-pyridyl 724 ″ O S * 4 2, 6-dimethyl-3-pyridyl 725 ″ O S * 5 2, 6-dimethyl-3-pyridyl 726 ″ O S * 6 2, 6-dimethyl-3-pyridyl 727 ″ O S * 7 2, 6-dimethyl-3-pyridyl 728 ″ O S * 8 2, 6-dimethyl-3-pyridyl 729 ″ O S * 9 2, 6-dimethyl-3-pyridyl 730 ″ O S * 14  2, 6-dimethyl-3-pyridyl 731 ″ S S * 1 2, 6-dimethyl-3-pyridyl 732 ″ S S * 2 2, 6-dimethyl-3-pyridyl 733 ″ S S * 3 2, 6-dimethyl-3-pyridyl 734 ″ S S * 4 2, 6-dimethyl-3-pyridyl 735 ″ S S * 5 2, 6-dimethyl-3-pyridyl 736 ″ S S * 6 2, 6-dimethyl-3-pyridyl 737 ″ S S * 7 2, 6-dimethyl-3-pyridyl 738 ″ S S * 8 2, 6-dimethyl-3-pyridyl 739 ″ S S * 9 2, 6-dimethyl-3-pyridyl 740 ″ S S * 14  2, 6-dimethyl-3-pyridyl * Single Bond

TABLE 38 Com- pound No.

X Y Z n Het 741

NH S * 1 2, 6-dimethyl-3- pyridyl 742 ″ NH S * 2 2, 6-dimethyl-3- pyridyl 743 ″ NH S * 3 2, 6-dimethyl-3- pyridyl 744 ″ NH S * 4 2, 6-dimethyl-3- pyridyl 745 ″ NH S * 5 2, 6-dimethyl-3- pyridyl 746 ″ NH S * 6 2, 6-dimethyl-3- pyridyl 747 ″ NH S * 7 2, 6-dimethyl-3- pyridyl 748 ″ NH S * 8 2, 6-dimethyl-3- pyridyl 749 ″ NH S * 9 2, 6-dimethyl-3- pyridyl 750 ″ NH S * 14  2, 6-dimethyl-3- pyridyl 751 ″ O S * 1 2, 6-diethyl-3- pyridyl 752 ″ O S * 2 2, 6-diethyl-3- pyridyl 753 ″ O S * 3 2, 6-diethyl-3- pyridyl 754 ″ O S * 4 2, 6-diethyl-3- pyridyl 755 ″ O S * 5 2, 6-diethyl-3- pyridyl 756 ″ O S * 6 2, 6-diethyl-3- pyridyl 757 ″ O S * 7 2, 6-diethyl-3- pyridyl 758 ″ O S * 8 2, 6-diethyl-3- pyridyl 759 ″ O S * 9 2, 6-diethyl-3- pyridyl 760 ″ O S * 14  2, 6-diethyl-3- pyridyl * Single Bond

TABLE 39 Com- pound No.

X Y Z n Het 761

S S * 1 2, 6-diethyl-3-pyridyl 762 ″ S S * 2 2, 6-diethyl-3-pyridyl 763 ″ S S * 3 2, 6-diethyl-3-pyridyl 764 ″ S S * 4 2, 6-diethyl-3-pyridyl 765 ″ S S * 5 2, 6-diethyl-3-pyridyl 766 ″ S S * 6 2, 6-diethyl-3-pyridyl 767 ″ S S * 7 2, 6-diethyl-3-pyridyl 768 ″ S S * 8 2, 6-diethyl-3-pyridyl 769 ″ S S * 9 2, 6-diethyl-3-pyridyl 770 ″ S S * 14  2, 6-diethyi-3-pyridyl 771 ″ NH S * 1 2, 6-diethyl-3-pyridyl 772 ″ NH S * 2 2, 6-diethyl-3-pyridyl 773 ″ NH S * 3 2, 6-diethyl-3-pyridyl 774 ″ NH S * 4 2, 6-diethyl-3-pyridyl 775 ″ NH S * 5 2, 6-diethyl-3-pyridyl 776 ″ NH S * 6 2, 6-diethyl-3-pyridyl 777 ″ NH S * 7 2, 6-diethyl-3-pyridyl 778 ″ NH S * 8 2, 6-diethyl-3-pyridyl 779 ″ NH S * 9 2, 6-diethyl-3-pyridyl 780 ″ NH S * 14  2, 6-diethyl-3-pyridyl * Single Bond

TABLE 40 Com- pound No.

X Y Z n Het 781

O S * 1 2, 4-bismethylthio-6- methyl-3-pyridyl 782 ″ O S * 2 2, 4-bismethylthio-6- methyl-3-pyridyl 783 ″ O S * 3 2, 4-bismethylthio-6- methyl-3-pyridyl 784 ″ O S * 4 2, 4-bismethylthio-6- methyl-3-pyridyl 785 ″ O S * 5 2, 4-bismethylthio-6- methyl-3-pyridyl 786 ″ O S * 6 2, 4-bismethylthio-6- methyl-3-pyridyl 787 ″ O S * 7 2, 4-bismethylthio-6- methyl-3-pyridyl 788 ″ O S * 8 2, 4-bismethylthio-6- methyl-3-pyridyl 789 ″ O S * 9 2, 4-bismethylthio-6- methyl-3-pyridyl 790 ″ O S * 14  2, 4-bismethylthio-6- methyl-3-pyridyl 791 ″ S S * 1 2, 4-bismethylthio-6- methyl-3-pyridyl 792 ″ S S * 2 2, 4-bismethylthio-6- methyl-3-pyridyl 793 ″ S S * 3 2, 4-bismethylthio-6- methyl-3-pyridyl 794 ″ S S * 4 2, 4-bismethylthio-6- methyl-3-pyridyl 795 ″ S S * 5 2, 4-bismethylthio-6- methyl-3-pyridyl 796 ″ S S * 6 2, 4-bismethylthio-6- methyl-3-pyridyl 797 ″ S S * 7 2, 4-bismethylthio-6- methyl-3-pyridyl 798 ″ S S * 8 2, 4-bismethylthio-6- methyl-3-pyridyl 799 ″ S S * 9 2, 4-bismethylthio-6- methyl-3-pyridyl 800 ″ S S * 14  2, 4-bismethylthio-6- methyl-3-pyridyl * Single Bond

TABLE 41 Com- pound No.

X Y Z n Het 801

NH S * 1 2, 4-bismethylthio-6-methyl-3-pyridyl 802 ib(id). NH S * 2 2, 4-bismethylthio-6-methyl-3-pyridyl 803 ib(id). NH S * 3 2, 4-bismethylthio-6-methyl-3-pyridyl 804 ib(id). NH S * 4 2, 4-bismethylthio-6-methyl-3-pyridyl 805 ib(id). NH S * 5 2, 4-bismethylthio-6-methyl-3-pyridyl 806 ib(id). NH S * 6 2, 4-bismethylthio-6-methyl-3-pyridyl 807 ib(id). NH S * 7 2, 4-bismethylthio-6-methyl-3-pyridyl 808 ib(id). NH S * 8 2, 4-bismethylthio-6-methyl-3-pyridyl 809 ib(id). NH S * 9 2, 4-bismethylthio-6-methyl-3-pyridyl 810 ib(id). NH S * 14  2, 4-bismethylthio-6-methyl-3-pyridyl 811 ib(id). O S * 1 2, 4-bisethylthio-6-methyl-3-pyridyl 812 ib(id). O S * 2 2, 4-bisethylthio-6-methyl-3-pyridyl 813 ib(id). O S * 3 2, 4-bisethylthio-6-methyl-3-pyridyl 814 ib(id). O S * 4 2, 4-bisethylthio-6-methyl-3-pyridyl 815 ib(id). O S * 5 2, 4-bisethylthio-6-methyl-3-pyridyl 816 ib(id). O S * 6 2, 4-bisethylthio-6-methyl-3-pyridyl 817 ib(id). O S * 7 2, 4-bisethylthio-6-methyl-3-pyridyl 818 ib(id). O S * 8 2, 4-bisethylthio-6-methyl-3-pyridyl 819 ib(id). O S * 9 2, 4-bisethylthio-6-methyl-3-pyridyl 820 ib(id). O S * 14  2, 4-bisethylthio-6-methyl-3-pyridyl * Single Bond

TABLE 42 Com- pound No.

X Y Z n Het 821

S S * 1 2, 4-bisethylthio-6-methyl-3-pyridyl 822 ib(id). S S * 2 2, 4-bisethylthio-6-methyl-3-pyridyl 823 ib(id). S S * 3 2, 4-bisethylthio-6-methyl-3-pyridyl 824 ib(id). S S * 4 2, 4-bisethylthio-6-methyl-3-pyridyl 825 ib(id). S S * 5 2, 4-bisethylthio-6-methyl-3-pyridyl 826 ib(id). S S * 6 2, 4-bisethylthio-6-methyl-3-pyridyl 827 ib(id). S S * 7 2, 4-bisethylthio-6-methyl-3-pyridyl 828 ib(id). S S * 8 2, 4-bisethylthio-6-methyl-3-pyridyl 829 ib(id). S S * 9 2, 4-bisethylthio-6-methyl-3-pyridyl 830 ib(id). S S * 14  2, 4-bisethylthio-6-methyl-3-pyridyl 831 ib(id). NH S * 1 2, 4-bisethylthio-6-methyl-3-pyridyl 832 ib(id). NH S * 2 2, 4-bisethylthio-6-methyl-3-pyridyl 833 ib(id). NH S * 3 2, 4-bisethylthio-6-methyl-3-pyridyl 834 ib(id). NH S * 4 2, 4-bisethylthlo-6-methyl-3-pyridyl 835 ib(id). NH S * 5 2, 4-bisethylthio-6-methyl-3-pyridyl 836 ib(id). NH S * 6 2, 4-bisethylthio-6-methyl-3-pyridyl 837 ib(id). NH S * 7 2, 4-bisethylthio-6-methyl-3-pyridyl 838 ib(id). NH S * 8 2, 4-bisethylthio-6-methyl-3-pyridyl 839 ib(id). NH S * 9 2, 4-bisethylthio-6-methyl-3-pyridyl 840 ib(id). NH S * 14  2, 4-bisethylthio-6-methyl-3-pyridyl * Single Bond

TABLE 43 Com- pound No.

X Y Z n Het 841

O S * 1 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 842 ib(id). O S * 2 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 843 ib(id). O S * 3 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 844 ib(id). O S * 4 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 845 ib(id). O S * 5 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 846 ib(id). O S * 6 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 847 ib(id). O S * 7 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 848 ib(id). O S * 8 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 849 ib(id). O S * 9 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 850 ib(id). O S * 14  2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 851 ib(id). S S * 1 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 852 ib(id). S S * 2 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 853 ib(id). S S * 3 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 854 ib(id). S S * 4 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 855 ib(id). S S * 5 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 856 ib(id). S S * 6 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 857 ib(id). S S * 7 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 858 ib(id). S S * 8 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 859 ib(id). S S * 9 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 860 ib(id). S S * 14  2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl * Single Bond

TABLE 44 Com- pound No.

X Y Z n Het 861

NH S * 1 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 862 ib(id). NH S * 2 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 863 ib(id). NH S * 3 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 864 ib(id). NH S * 4 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 865 ib(id). NH S * 5 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 866 ib(id). NH S * 6 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 867 ib(id). NH S * 7 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 868 ib(id). NH S * 8 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 869 ib(id). NH S * 9 2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 870 ib(id). NH S * 14  2, 4-bis(iso-propylthio)-6-methyl-3-pyridyl 871 ib(id). O S * 1 2, 4-dimethoxy-6-methyl-3-pyridyl 872 ib(id). O S * 2 2, 4-dimethoxy-6-methyl-3-pyridyl 873 ib(id). O S * 3 2, 4-dimethoxy-6-methyl-3-pyridyl 874 ib(id). O S * 4 2, 4-dimethoxy-6-methyl-3-pyridyl 875 ib(id). O S * 5 2, 4-dimethoxy-6-methyl-3-pyridyl 876 ib(id). O S * 6 2, 4-dimethoxy-6-methyl-3-pyridyl 877 ib(id). O S * 7 2, 4-dimethoxy-6-methyl-3-pyridyl 878 ib(id). O S * 8 2, 4-dimethoxy-6-methyl-3-pyridyl 879 ib(id). O S * 9 2, 4-dimethoxy-6-methyl-3-pyridyl 880 ib(id). O S * 14  2, 4-dimethoxy-6-methyl-3-pyridyl * Single Bond

TABLE 45 Com- pound No.

X Y Z n Het 881

S S * 1 2, 4-dimethoxy- 6-methyl-3-pyridyl 882 ib(id). S S * 2 2, 4-dimethoxy- 6-methyl-3-pyridyl 883 ib(id). S S * 3 2, 4-dimethoxy- 6-methyl-3-pyridyl 884 ib(id). S S * 4 2, 4-dimethoxy- 6-methyl-3-pyridyl 885 ib(id). S S * 5 2, 4-dimethoxy- 6-methyl-3-pyridyl 886 ib(id). S S * 6 2, 4-dimethoxy- 6-methyl-3-pyridyl 887 ib(id). S S * 7 2, 4-dimethoxy- 6-methyl-3-pyridyl 888 ib(id). S S * 8 2, 4-dimethoxy- 6-methyl-3-pyridyl 889 ib(id). S S * 9 2, 4-dimethoxy- 6-methyl-3-pyridyl 890 ib(id). S S * 14  2, 4-dimethoxy- 6-methyl-3-pyridyl 891 ib(id). NH S * 1 2, 4-dimethoxy- 6-methyl-3-pyridyl 892 ib(id). NH S * 2 2, 4-dimethoxy- 6-methyl-3-pyridyl 893 ib(id). NH S * 3 2, 4-dimethoxy- 6-methyl-3-pyridyl 894 ib(id). NH S * 4 2, 4-dimethoxy- 6-methyl-3-pyridyl 895 ib(id). NH S * 5 2, 4-dimethoxy- 6-methyl-3-pyridyl 896 ib(id). NH S * 6 2, 4-dimethoxy- 6-methyl-3-pyridyl 897 ib(id). NH S * 7 2, 4-dimethoxy- 6-methyl-3-pyridyl 898 ib(id). NH S * 8 2, 4-dimethoxy- 6-methyl-3-pyridyl 899 ib(id). NH S * 9 2, 4-dimethoxy- 6-methyl-3-pyridyl 900 ib(id). NH S * 14  2, 4-dimethoxy- 6-methyl-3-pyridyl * Single Bond

TABLE 46 Com- pound No.

X Y Z n Het 901

O S * 1 2, 4, 6-trimethyl-3- pyridyl 902 ib(id). O S * 2 2, 4, 6-trimethyl-3- pyridyl 903 ib(id). O S * 3 2, 4, 6-trimethyl-3- pyridyl 904 ib(id). O S * 4 2, 4, 6-trimethyl-3- pyridyl 905 ib(id). O S * 5 2, 4, 6-trimethyl-3- pyridyl 906 ib(id). O S * 6 2, 4, 6-trimethyl-3- pyridyl 907 ib(id). O S * 7 2, 4, 6-trimethyl-3- pyridyl 908 ib(id). O S * 8 2, 4, 6-trimethyl-3- pyridyl 909 ib(id). O S * 9 2, 4, 6-trimethyl-3- pyridyl 910 ib(id). O S * 14  2, 4, 6-trimethyl-3- pyridyl 911 ib(id). S S * 1 2, 4, 6-trimethyl-3- pyridyl 912 ib(id). S S * 2 2, 4, 6-trimethyl-3- pyridyl 913 ib(id). S S * 3 2, 4, 6-trimethyl-3- pyridyl 914 ib(id). S S * 4 2, 4, 6-trimethyl-3- pyridyl 915 ib(id). S S * 5 2, 4, 6-trimethyl-3- pyridyl 916 ib(id). S S * 6 2, 4, 6-trimethyl-3- pyridyl 917 ib(id). S S * 7 2, 4, 6-trimethyl-3- pyridyl 918 ib(id). S S * 8 2, 4, 6-trimethyl-3- pyridyl 919 ib(id). S S * 9 2, 4, 6-trimethyl-3- pyridyl 920 ib(id). S S * 14  2, 4, 6-trimethyl-3- pyridyl * Single Bond

TABLE 47 Com- pound No.

X Y Z n Het 921

NH S * 1 2, 4, 6-trimethyl-3- pyridyl 922 ib(id). NH S * 2 2, 4, 6-trimethyl-3- pyridyl 923 ib(id). NH S * 3 2, 4, 6-trimethyl-3- pyridyl 924 ib(id). NH S * 4 2, 4, 6-trimethyl-3- pyridyl 925 ib(id). NH S * 5 2, 4, 6-trimethyl-3- pyridyl 926 ib(id). NH S * 6 2, 4, 6-trimethyl-3- pyridyl 927 ib(id). NH S * 7 2, 4, 6-trimethyl-3- pyridyl 928 ib(id). NH S * 8 2, 4, 6-trimethyl-3- pyridyl 929 ib(id). NH S * 9 2, 4, 6-trimethyl-3- pyridyl 930 ib(id). NH S * 14  2, 4, 6-trimethyl-3- pyridyl 931 ib(id). O S * 1 4-ethyl-2, 6-dimethyl- 3-pyridyl 932 ib(id). O S * 2 4-ethyl-2, 6-dimethyl- 3-pyridyl 933 ib(id). O S * 3 4-ethyl-2, 6-dimethyl- 3-pyridyl 934 ib(id). O S * 4 4-ethyl-2, 6-dimethyl- 3-pyridyl 935 ib(id). O S * 5 4-ethyl-2, 6-dimethyl- 3-pyridyl 936 ib(id). O S * 6 4-ethyl-2, 6-dimethyl- 3-pyridyl 937 ib(id). O S * 7 4-ethyl-2, 6-dimethyl- 3-pyridyl 938 ib(id). O S * 8 4-ethyl-2, 6-dimethyl- 3-pyridyl 939 ib(id). O S * 9 4-ethyl-2, 6-dimethyl- 3-pyridyl 940 ib(id). O S * 14  4-ethyl-2, 6-dimethyl- 3-pyridyl * Single Bond

TABLE 48 Com- pound No.

X Y Z n Het 941

S S * 1 4-ethyl-2, 6-dimethyl- 3-pyridyl 942 ib(id). S S * 2 4-ethyl-2, 6-dimethyl- 3-pyridyl 943 ib(id). S S * 3 4-ethyl-2, 6-dimethyl- 3-pyridyl 944 ib(id). S S * 4 4-ethyl-2, 6-dimethyl- 3-pyridyl 945 ib(id). S S * 5 4-ethyl-2, 6-dimethyl- 3-pyridyl 946 ib(id). S S * 6 4-ethyl-2, 6-dimethyl- 3-pyridyl 947 ib(id). S S * 7 4-ethyl-2, 6-dimethyl- 3-pyridyl 948 ib(id). S S * 8 4-ethyl-2, 6-dimethyl- 3-pyridyl 949 ib(id). S S * 9 4-ethyl-2, 6-dimethyl- 3-pyridyl 950 ib(id). S S * 14  4-ethyl-2, 6-dimethyl- 3-pyridyl 951 ib(id). NH S * 1 4-ethyl-2, 6-dimethyl- 3-pyridyl 952 ib(id). NH S * 2 4-ethyl-2, 6-dimethyl- 3-pyridyl 953 ib(id). NH S * 3 4-ethyl-2, 6-dimethyl- 3-pyridyl 954 ib(id). NH S * 4 4-ethyl-2, 6-dimethyl- 3-pyridyl 955 ib(id). NH S * 5 4-ethyl-2, 6-dimethyl- 3-pyridyl 956 ib(id). NH S * 6 4-ethyl-2, 6-dimethyl- 3-pyridyl 957 ib(id). NH S * 7 4-ethyl-2, 6-dimethyl- 3-pyridyl 958 ib(id). NH S * 8 4-ethyl-2, 6-dimethyl- 3-pyridyl 959 ib(id). NH S * 9 4-ethyl-2, 6-dimethyl- 3-pyridyl 960 ib(id). NH S * 14  4-ethyl-2, 6-dimethyl- 3-pyridyl * Single Bond

TABLE 49 Com- pound No.

X Y Z n Het 961

O S * 1 2, 4-dichloro-6-methyl-3- pyridyl 962 ib(id). O S * 2 2, 4-dichloro-6-methyl-3- pyridyl 963 ib(id). O S * 3 2, 4-dichloro-6-methyl-3- pyridyl 964 ib(id). O S * 4 2, 4-dichloro-6-methyl-3- pyridyl 965 ib(id). O S * 5 2, 4-dichloro-6-methyl-3- pyridyl 966 ib(id). O S * 6 2, 4-dichloro-6-methyl-3- pyridyl 967 ib(id). O S * 7 2, 4-dichloro-6-methyl-3- pyridyl 968 ib(id). O S * 8 2, 4-dichloro-6-methyl-3- pyridyl 969 ib(id). O S * 9 2, 4-dichloro-6-methyl-3- pyridyl 970 ib(id). O S * 14  2, 4-dichloro-6-methyl-3- pyridyl 971 ib(id). S S * 1 2, 4-dichloro-6-methyl-3- pyridyl 972 ib(id). S S * 2 2, 4-dichloro-6-methyl-3- pyridyl 973 ib(id). S S * 3 2, 4-dichloro-6-methyl-3- pyridyl 974 ib(id). S S * 4 2, 4-dichloro-6-methyl-3- pyridyl 975 ib(id). S S * 5 2, 4-dichloro-6-methyl-3- pyridyl 976 ib(id). S S * 6 2, 4-dichloro-6-methyl-3- pyridyl 977 ib(id). S S * 7 2, 4-dichloro-6-methyl-3- pyridyl 978 ib(id). S S * 8 2, 4-dichloro-6-methyl-3- pyridyl 979 ib(id). S S * 9 2, 4-dichloro-6-methyl-3- pyridyl 980 ib(id). S S * 14  2, 4-dichloro-6-methyl-3- pyridyl * Single Bond

TABLE 50 Com- pound No.

X Y Z n Het 981

NH S * 1 2, 4-dichloro-6- methyl-3-pyridyl 982 ib(id). NH S * 2 2, 4-dichloro-6- methyl-3-pyridyl 983 ib(id). NH S * 3 2, 4-dichloro-6- methyl-3-pyridyl 984 ib(id). NH S * 4 2, 4-dichloro-6- methyl-3-pyridyl 985 ib(id). NH S * 5 2, 4-dichloro-6- methyl-3-pyridyl 986 ib(id). NH S * 6 2, 4-dichloro-6- methyl-3-pyridyl 987 ib(id). NH S * 7 2, 4-dichloro-6- methyl-3-pyridyl 988 ib(id). NH S * 8 2, 4-dichloro-6- methyl-3-pyridyl 989 ib(id). NH S * 9 2, 4-dichloro-6- methyl-3-pyridyl 990 ib(id). NH S * 14  2, 4-dichloro-6- methyl-3-pyridyl 991 ib(id). O S * 1 4, 6-bismethylthio- 5-pyrimidyl 992 ib(id). O S * 2 4, 6-bismethylthio- 5-pyrimidyl 993 ib(id). O S * 3 4, 6-bismethylthio- 5-pyrimidyl 994 ib(id). O S * 4 4, 6-bismethylthio- 5-pyrimidyl 995 ib(id). O S * 5 4, 6-bismethylthio- 5-pyrimidyl 996 ib(id). O S * 6 4, 6-bismethylthio- 5-pyrimidyl 997 ib(id). O S * 7 4, 6-bismethylthio- 5-pyrimidyl 998 ib(id). O S * 8 4, 6-bismethylthio- 5-pyrimidyl 999 ib(id). O S * 9 4, 6-bismethylthio- 5-pyrimidyl 1000  ib(id). O S * 14  4, 6-bismethylthio- 5-pyrimidyl * Single Bond

TABLE 51 Com- pound No.

X Y Z n Het 1001

S S * 1 4,6-bismethylthio-5-py- rimidyl 1002 ib (id). S S * 2 4,6-bismethylthio-5-py- rimidyl 1003 ib (id). S S * 3 4,6-bismethylthio-5-py- rimidyl 1004 ib (id). S S * 4 4,6-bismethylthio-5-py- rimidyl 1005 ib (id). S S * 5 4,6-bismethylthio-5-py- rimidyl 1006 ib (id). S S * 6 4,6-bismethylthio-5-py- rimidyl 1007 ib (id). S S * 7 4,6-bismethylthio-5-py- rimidyl 1008 ib (id). S S * 8 4,6-bismethylthio-5-py- rimidyl 1009 ib (id). S S * 9 4,6-bismethylthio-5-py- rimidyl 1010 ib (id). S S * 14 4,6-bismethylthio-5-py- rimidyl 1011 ib (id). NH S * 1 4,6-bismethylthio-5-py- rimidyl 1012 ib (id). NH S * 2 4,6-bismethylthio-5-py- rimidyl 1013 ib (id). NH S * 3 4,6-bismethylthio-5-py- rimidyl 1014 ib (id). NH S * 4 4,6-bismethylthio-5-py- rimidyl 1015 ib (id). NH S * 5 4,6-bismethylthio-5-py- rimidyl 1016 ib (id). NH S * 6 4,6-bismethylthio-5-py- rimidyl 1017 ib (id). NH S * 7 4,6-bismethylthio-5-py- rimidyl 1018 ib (id). NH S * 8 4,6-bismethylthio-5-py- rimidyl 1019 ib (id). NH S * 9 4,6-bismethylthio-5-py- rimidyl 1020 ib (id). NH S * 14 4,6-bismethylthio-5-py- rimidyl *Single Bond

TABLE 52 Com- pound No.

X Y Z n Het 1021

O S * 1 4,6-bisethylthio-5-py- rimidyl 1022 ib (id). O S * 2 4,6-bnisethylthio-5-py- rimidyl 1023 ib (id). O S * 3 4,6-bnisethylthio-5-py- rimidyl 1024 ib (id). O S * 4 4,6-bnisethylthio-5-py- rimidyl 1025 ib (id). O S * 5 4,6-bnisethylthio-5-py- rimidyl 1026 ib (id). O S * 6 4,6-bnisethylthio-5-py- rimidyl 1027 ib (id). O S * 7 4,6-bnisethylthio-5-py- rimidyl 1028 ib (id). O S * 8 4,6-bnisethylthio-5-py- rimidyl 1029 ib (id). O S * 9 4,6-bnisethylthio-5-py- rimidyl 1030 ib (id). O S * 14 4,6-bnisethylthio-5-py- rimidyl 1031 ib (id). S S * 1 4,6-bnisethylthio-5-py- rimidyl 1032 ib (id). S S * 2 4,6-bnisethylthio-5-py- rimidyl 1033 ib (id). S S * 3 4,6-bnisethylthio-5-py- rimidyl 1034 ib (id). S S * 4 4,6-bnisethylthio-5-py- rimidyl 1035 ib (id). S S * 5 4,6-bnisethylthio-5-py- rimidyl 1036 ib (id). S S * 6 4,6-bnisethylthio-5-py- rimidyl 1037 ib (id). S S * 7 4,6-bnisethylthio-5-py- rimidyl 1038 ib (id). S S * 8 4,6-bnisethylthio-5-py- rimidyl 1039 ib (id). S S * 9 4,6-bnisethylthio-5-py- rimidyl 1040 ib (id). S S * 14 4,6-bnisethylthio-5-py- rimidyl *Single Bond

TABLE 53 Com- pound No.

X Y Z n Het 1041

NH S * 1 4,6-bisethylthio-5-py- rimidyl 1042 ib (id). NH S * 2 4,6-bisethylthio-5-py- rimidyl 1043 ib (id). NH S * 3 4,6-bisethylthio-5-py- rimidyl 1044 ib (id). NH S * 4 4,6-bisethylthio-5-py- rimidyl 1045 ib (id). NH S * 5 4,6-bisethylthio-5-py- rimidyl 1046 ib (id). NH S * 6 4,6-bisethylthio-5-py- rimidyl 1047 ib (id). NH S * 7 4,6-bisethylthio-5-py- rimidyl 1048 ib (id). NH S * 8 4,6-bisethylthio-5-py- rimidyl 1049 ib (id). NH S * 9 4,6-bisethylthio-5-py- rimidyl 1050 ib (id). NH S * 14 4,6-bisethylthio-5-py- rimidyl 1051 ib (id). O S * 1 4,6-bis(iso-propylthio)-5- pyrimidyl 1052 ib (id). O S * 2 4,6-bis(iso-propylthio)-5- pyrimidyl 1053 ib (id). O S * 3 4,6-bis(iso-propylthio)-5- pyrimidyl 1054 ib (id). O S * 4 4,6-bis(iso-propylthio)-5- pyrimidyl 1055 ib (id). O S * 5 4,6-bis(iso-propylthio)-5- pyrimidyl 1056 ib (id). O S * 6 4,6-bis(iso-propylthio)-5- pyrimidyl 1057 ib (id). O S * 7 4,6-bis(iso-propylthio)-5- pyrimidyl 1058 ib (id). O S * 8 4,6-bis(iso-propylthio)-5- pyrimidyl 1059 ib (id). O S * 9 4,6-bis(iso-propylthio)-5- pyrimidyl 1060 ib (id). O S * 14 4,6-bis(iso-propylthio)-5- pyrimidyl *Single Bond

TABLE 54 Com- pound No.

X Y Z n Het 1061

S S * 1 4,6-bis(iso-propylthio)- 5-pyrimidyl 1062 ib (id). S S * 2 4,6-bis(iso-propylthio)- 5-pyrimidyl 1063 ib (id). S S * 3 4,6-bis(iso-propylthio)- 5-pyrimidyl 1064 ib (id). S S * 4 4,6-bis(iso-propylthio)- 54-pyrimidyl 1065 ib (id). S S * 5 4,6-bis(iso-propylthio)- 5-pyrimidyl 1066 ib (id). S S * 6 4,6-bis(iso-propylthio)- 5-pyrimidyl 1067 ib (id). S S * 7 4,6-bis(iso-propylthio)- 5-pyrimidyl 1068 ib (id). S S * 8 4,6-bis(iso-propylthio)- 5-pyrimidyl 1069 ib (id). S S * 9 4,6-bis(iso-propylthio)- 5-pyrimidyl 1070 ib (id). S S * 14 4,6-bis(iso-propylthio)- 5-pyrimidyl 1071 ib (id). NH S * 1 4,6-bis(iso-propylthio)- 5-pyrimidyl 1072 ib (id). NH S * 2 4,6-bis(iso-propylthio)- 5-pyrimidyl 1073 ib (id). NH S * 3 4,6-bis(iso-propylthio)- 5-pyrimidyl 1074 ib (id). NH S * 4 4,6-bis(iso-propylthio)- 5-pyrimidyl 1075 ib (id). NH S * 5 4,6-bis(iso-propylthio)- 5-pyrimidyl 1076 ib (id). NH S * 6 4,6-bis(iso-propylthio)- 5-pyrimidyl 1077 ib (id). NH S * 7 4,6-bis(iso-propylthio)- 5-pyrimidyl 1078 ib (id). NH S * 8 4,6-bis(iso-propylthio)- 5-pyrimidyl 1079 ib (id). NH S * 9 4,6-bis(iso-propylthio)- 5-pyrimidyl 1080 ib (id). NH S * 14 4,6-bis(iso-propylthio)- 5-pyrimidyl *Single Bond

TABLE 55 Com- pound No.

X Y Z n Het 1081

O S * 1 4,6-dimethoxy-5-pyrimidyl 1082 ib (id). O S * 2 4,6-dimethoxy-5-pyrimidyl 1083 ib (id). O S * 3 4,6-dimethoxy-5-pyrimidyl 1084 ib (id). O S * 4 4,6-dimethoxy-5-pyrimidyl 1085 ib (id). O S * 5 4,6-dimethoxy-5-pyrimidyl 1086 ib (id). O S * 6 4,6-dimethoxy-5-pyrimidyl 1087 ib (id). O S * 7 4,6-dimethoxy-5-pyrimidyl 1088 ib (id). O S * 8 4,6-dimethoxy-5-pyrimidyl 1089 ib (id). O S * 9 4,6-dimethoxy-5-pyrimidyl 1090 ib (id). O S * 14 4,6-dimethoxy-5-pyrimidyl 1091 ib (id). S S * 1 4,6-dimethoxy-5-pyrimidyl 1092 ib (id). S S * 2 4,6-dimethoxy-5-pyrimidyl 1093 ib (id). S S * 3 4,6-dimethoxy-5-pyrimidyl 1094 ib (id). S S * 4 4,6-dimethoxy-5-pyrimidyl 1095 ib (id). S S * 5 4,6-dimethoxy-5-pyrimidyl 1096 ib (id). S S * 6 4,6-dimethoxy-5-pyrimidyl 1097 ib (id). S S * 7 4,6-dimethoxy-5-pyrimidyl 1098 ib (id). S S * 8 4,6-dimethoxy-5-pyrimidyl 1099 ib (id). S S * 9 4,6-dimethoxy-5-pyrimidyl 1100 ib (id). S S * 14 4,6-dimethoxy-5-pyrimidyl *Single Bond

TABLE 56 Com- pound No.

X Y Z n Het 1101

NH S * 1 4,6-dichloro-2-methyl-5- pyrimidyl 1102 ib (id). NH S * 2 4,6-dichloro-2-methyl-5- pyrimidyl 1103 ib (id). NH S * 3 4,6-dichloro-2-methyl-5- pyrimidyl 1104 ib (id). NH S * 4 4,6-dichloro-2-methyl-5- pyrimidyl 1105 ib (id). NH S * 5 4,6-dichloro-2-methyl-5- pyrimidyl 1106 ib (id). NH S * 6 4,6-dichloro-2-methyl-5- pyrimidyl 1107 ib (id). NH S * 7 4,6-dichloro-2-methyl-5- pyrimidyl 1108 ib (id). NH S * 8 4,6-dichloro-2-methyl-5- pyrimidyl 1109 ib (id). NH S * 9 4,6-dichloro-2-methyl-5- pyrimidyl 1110 ib (id). NH S * 14 4,6-dichloro-2-methyl-5- pyrimidyl 1111 ib (id). O S * 1 4,6-dichloro-2-methyl-5- pyrimidyl 1112 ib (id). O S * 2 4,6-dichloro-2-methyl-5- pyrimidyl 1113 ib (id). O S * 3 4,6-dichloro-2-methyl-5- pyrimidyl 1114 ib (id). O S * 4 4,6-dichloro-2-methyl-5- pyrimidyl 1115 ib (id). O S * 5 4,6-dichloro-2-methyl-5- pyrimidyl 1116 ib (id). O S * 6 4,6-dichloro-2-methyl-5- pyrimidyl 1117 ib (id). O S * 7 4,6-dichloro-2-methyl-5- pyrimidyl 1118 ib (id). O S * 8 4,6-dichloro-2-methyl-5- pyrimidyl 1119 ib (id). O S * 9 4,6-dichloro-2-methyl-5- pyrimidyl 1120 ib (id). O S * 14 4,6-dichloro-2-methyl-5- pyrimidyl *Single Bond

TABLE 57 Com- pound No.

X Y Z n Het 1121

S S * 1 4,6-bis(dimethylamino)-5- pyrimidyl 1122 ib (id). S S * 2 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1123 ib (id). S S * 3 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1124 ib (id). S S * 4 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1125 ib (id). S S * 5 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1126 ib (id). S S * 6 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1127 ib (id). S S * 7 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1128 ib (id). S S * 8 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1129 ib (id). S S * 9 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1130 ib (id). S S * 14 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1131 ib (id). NH S * 1 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1122 ib (id). NH S * 2 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1133 ib (id). NH S * 3 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1134 ib (id). NH S * 4 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1135 ib (id). NH S * 5 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1136 ib (id). NH S * 6 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1137 ib (id). NH S * 7 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1138 ib (id). NH S * 8 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1139 ib (id). NH S * 9 4,6-bis(ddimnethylthio)- 5-pyrimidyl 1140 ib (id). NH S * 14 4,6-bis(ddimnethylthio)- 5-pyrimidyl *Single Bond

TABLE 58 Com- pound No.

X Y Z n Het 1141

O S * 1 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1142 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1143 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1144 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1145 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1146 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1147 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1148 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1149 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1150 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1151 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1152 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1153 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1154 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1155 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1156 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1157 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1158 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1159 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl 1160 ib (id). O S * 2 4,6-bismethylthio-2-methyl- 5-pyrimidyl *Single Bond

TABLE 59 Com- pound No.

X Y Z n Het 1161

NH S * 1 4,6-bismethylthio-2- methyl-5-pyrimidyl 1162 ib (id). NH S * 2 4,6-bismethylthio-2- methyl-5-pyrimidyl 1163 ib (id). NH S * 3 4,6-bismethylthio-2- methyl-5-pyrimidyl 1164 ib (id). NH S * 4 4,6-bismethylthio-2- methyl-5-pyrimidyl 1165 ib (id). NH S * 5 4,6-bismethylthio-2- methyl-5-pyrimidyl 1166 ib (id). NH S * 6 4,6-bismethylthio-2- methyl-5-pyrimidyl 1167 ib (id). NH S * 7 4,6-bismethylthio-2- methyl-5-pyrimidyl 1168 ib (id). NH S * 8 4,6-bismethylthio-2- methyl-5-pyrimidyl 1169 ib (id). NH S * 9 4,6-bismethylthio-2- methyl-5-pyrimidyl 1170 ib (id). NH S * 14 4,6-bismethylthio-2- methyl-5-pyrimidyl 1171 ib (id). NH S * 1 4,6-bismethylthio-2- methyl-5-pyrimidyl 1172 ib (id). O S * 2 4,6-bismethylthio-2- methyl-5-pyrimidyl 1173 ib (id). O S * 3 4,6-bismethylthio-2- methyl-5-pyrimidyl 1174 ib (id). O S * 4 4,6-bismethylthio-2- methyl-5-pyrimidyl 1175 ib (id). O S * 5 4,6-bismethylthio-2- methyl-5-pyrimidyl 1176 ib (id). O S * 6 4,6-bismethylthio-2- methyl-5-pyrimidyl 1177 ib (id). O S * 7 4,6-bismethylthio-2- methyl-5-pyrimidyl 1178 ib (id). O S * 8 4,6-bismethylthio-2- methyl-5-pyrimidyl 1179 ib (id). O S * 9 4,6-bismethylthio-2- methyl-5-pyrimidyl 1180 ib (id). O S * 14 4,6-bismethylthio-2- methyl-5-pyrimidyl *Single Bond

TABLE 60 Com- pound No.

X Y Z n Het 1181

S S * 1 2,4,6-trimethoxy-5- pyrimidyl 1182 ib (id). S S * 2 2,4,6-trimethoxy-5- pyrimidyl 1183 ib (id). S S * 3 2,4,6-trimethoxy-5- pyrimidyl 1184 ib (id). S S * 4 2,4,6-trimethoxy-5- pyrimidyl 1185 ib (id). S S * 5 2,4,6-trimethoxy-5- pyrimidyl 1186 ib (id). S S * 6 2,4,6-trimethoxy-5- pyrimidyl 1187 ib (id). S S * 7 2,4,6-trimethoxy-5- pyrimidyl 1188 ib (id). S S * 8 2,4,6-trimethoxy-5- pyrimidyl 1189 ib (id). S S * 9 2,4,6-trimethoxy-5- pyrimidyl 1190 ib (id). S S * 14 2,4,6-trimethoxy-5- pyrimidyl 1191 ib (id). NH S * 1 2,4,6-trimethoxy-5- pyrimidyl 1192 ib (id). NH S * 2 2,4,6-trimethoxy-5- pyrimidyl 1193 ib (id). NH S * 3 2,4,6-trimethoxy-5- pyrimidyl 1194 ib (id). NH S * 4 2,4,6-trimethoxy-5- pyrimidyl 1195 ib (id). NH S * 5 2,4,6-trimethoxy-5- pyrimidyl 1196 ib (id). NH S * 6 2,4,6-trimethoxy-5- pyrimidyl 1197 ib (id). NH S * 7 2,4,6-trimethoxy-5- pyrimidyl 1198 ib (id). NH S * 8 2,4,6-trimethoxy-5- pyrimidyl 1199 ib (id). NH S * 9 2,4,6-trimethoxy-5- pyrimidyl 1200 ib (id). NH S * 14 2,4,6-trimethoxy-5- pyrimidyl *Single Bond

TABLE 61 Compound No.

 X  Y  Z  n  Het 1201

O SO * 5 2-methylthio- 3-pyridyl 1202 ib(id). O SO₂ * 5 2-methylthio- 3-pyridyl 1203 ib(id). O NH * 5 2-methylthio- 3-pyridyl 1204 ib(id). S SO * 5 2-methylthio- 3-pyridyl 1205 ib(id). S SO₂ * 5 2-methylthio- 3-pyridyl 1206 ib(id). S NH * 5 2-methylthio- 3-pyridyl 1207 ib(id). NH SO * 5 2-methylthio- 3-pyridyl 1208 ib(id). NH SO₂ * 5 2-methylthio- 3-pyridyl 1209 ib(id). NH NH * 5 2-methylthio- 3-pyridyl 1210 ib(id). O SO NH 6 2-methylthio- 3-pyridyl 1211 ib(id). O SO₂ NH 6 2-methylthio- 3-pyridyl 1212 ib(id). O NH NH 6 2-methylthio- 3-pyridyl 1213 ib(id). S SO NH 6 2-methylthio- 3-pyridyl 1214 ib(id). S SO₂ NH 6 2-methylthio- 3-pyridyl 1215 ib(id). S NH NH 6 2-methylthio- 3-pyridyl 1216 ib(id). NH SO NH 6 2-methylthio- 3-pyridyl 1217 ib(id). NH SO₂ NH 6 2-methylthio- 3-pyridyl 1218 ib(id). NH NH NH 6 2-methylthio- 3-pyridyl *: Single Bond

TABLE 62 Compound No.

X Y Z n Het 1219

O SO * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1220 ib(id). O SO₂ * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1221 ib(id). O NH * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1222 ib(id). S SO * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1223 ib(id). S SO₂ * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1224 ib(id). S NH * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1225 ib(id). NH SO * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1226 ib(id). NH SO₂ * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1227 ib(id). NH NH * 5 2,4-bismethylthio-6-methyl-3-pyridyl 1228 ib(id). O SO NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1229 ib(id). O SO₂ NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1230 ib(id). O NH NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1231 ib(id). S SO NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1232 ib(id). S SO₂ NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1233 ib(id). S NH NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1234 ib(id). NH SO NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1235 ib(id). NH NH NH 6 2,4-bismethylthio-6-methyl-3-pyridyl 1236 ib(id). NH NH NH 6 2,4-bismethylthio-6-methyl-3-pyridyl *: Single Bond

TABLE 63 Compound No.

X Y Z n Het 1237

O S Single Bond 5

1238

O S Single Bond 5

1239

O S Single Bond 8

1240

O S Single Bond 8

1241

O S Single Bond 5

1242

O S Single Bond 5

1243

O S Single Bond 8

1244

O S Single Bond 8

1245

S S Single Bond 1

1246

NH S Single Bond 1

TABLE 64 Compound No.

X Y Z n Het 1247

O S Single Bond 1

1248

O S Single Bond 2

1249

O S Single Bond 3

1250

O S Single Bond 4

1251

O S Single Bond 5

1252

O S Single Bond 6

1253

O S Single Bond 7

1254

O S Single Bond 8

1255

O S Single Bond 9

1256

O S Single Bond 14

TABLE 65 Compound No.

X Y Z n Het 1257

O S Single Bond 1

1258

O S Single Bond 2

1259

O S Single Bond 3

1260

O S Single Bond 4

1261

O S Single Bond 5

1262

O S Single Bond 6

1263

O S Single Bond 7

1264

O S Single Bond 8

1265

O S Single Bond 9

1266

O S Single Bond 14

TABLE 66 Compound No.

X Y Z n Het 1267

O S Single Bond 1

1268

O S Single Bond 2

1269

O S Single Bond 3

1270

O S Single Bond 4

1271

O S Single Bond 5

1272

O S Single Bond 6

1273

O S Single Bond 7

1274

O S Single Bond 8

1275

O S Single Bond 9

1276

O S Single Bond 14

TABLE 67 Compound No.

X Y Z n Het 1277

O S Single Bond 1

1278

O S Single Bond 2

1279

O S Single Bond 3

1280

O S Single Bond 4

1281

O S Single Bond 5

1282

O S Single Bond 6

1283

O S Single Bond 7

1284

O S Single Bond 8

1285

O S Single Bond 9

1286

O S Single Bond 14

TABLE 68 Compound No.

X Y Z n Het 1287

O S Single Bond 1

1288

O S Single Bond 2

1289

O S Single Bond 3

1290

O S Single Bond 4

1291

O S Single Bond 5

1292

O S Single Bond 6

1293

O S Single Bond 7

1294

O S Single Bond 8

1295

O S Single Bond 9

1296

O S Single Bond 14

TABLE 69 Compound No.

X Y Z n Het 1297

O S Single Bond 1

1298

O S Single Bond 2

1299

O S Single Bond 3

1300

O S Single Bond 4

1301

O S Single Bond 5

1302

O S Single Bond 6

1303

O S Single Bond 7

1304

O S Single Bond 8

1305

O S Single Bond 9

1306

O S Single Bond 14

TABLE 70 Compound No.

X Y Z n Het 1307

O S Single Bond 1

1308

O S Single Bond 2

1309

O S Single Bond 3

1310

O S Single Bond 4

1311

O S Single Bond 5

1312

O S Single Bond 6

1313

O S Single Bond 7

1314

O S Single Bond 8

1315

O S Single Bond 9

1316

O S Single Bond 14

TABLE 71 Compound No.

X Y Z n Het 1317

O S Single Bond 1

1318

O S Single Bond 2

1319

O S Single Bond 3

1320

O S Single Bond 4

1321

O S Single Bond 5

1322

O S Single Bond 6

1323

O S Single Bond 7

1324

O S Single Bond 8

1325

O S Single Bond 9

1326

O S Single Bond 14

TABLE 72 Compound No.

X Y Z n Het 1327

O S Single Bond 1

1328

O S Single Bond 2

1329

O S Single Bond 3

1330

O S Single Bond 4

1331

O S Single Bond 5

1332

O S Single Bond 6

1333

O S Single Bond 7

1334

O S Single Bond 8

1335

O S Single Bond 9

1336

O S Single Bond 14

TABLE 73 Com- pound No.

X Y Z n Het , 1337

O S * 1 4-methyl-6-methylthio- 3-pyridyl 1338 ib (id). O S * 2 4-methyl-6-methylthio- 3-pyridyl 1339 ib (id). O S * 3 4-methyl-6-methylthio- 3-pyridyl 1340 ib (id). O S * 4 4-methyl-6-methylthio- 3-pyridyl 1341 ib (id). O S * 5 4-methyl-6-methylthio- 3-pyridyl 1342 ib (id). O S * 6 4-methyl-6-methylthio- 3-pyridyl 1343 ib (id). O S * 7 4-methyl-6-methylthio- 3-pyridyl 1344 ib (id). O S * 8 4-methyl-6-methylthio- 3-pyridyl 1345 ib (id). O S * 9 4-methyl-6-methylthio- 3-pyridyl 1346 ib (id). O S * 14 4-methyl-6-methylthio- 3-pyridyl 1347 ib (id). S S * 1 4-methyl-6-methylthio- 3-pyridyl 1348 ib (id). S S * 2 4-methyl-6-methylthio- 3-pyridyl 1349 ib (id). S S * 3 4-methyl-6-methylthio- 3-pyridyl 1350 ib (id). S S * 4 4-methyl-6-methylthio- 3-pyridyl 1351 ib (id). S S * 5 4-methyl-6-methylthio- 3-pyridyl 1352 ib (id). S S * 6 4-methyl-6-methylthio- 3-pyridyl 1353 ib (id). S S * 7 4-methyl-6-methylthio- 3-pyridyl 1354 ib (id). S S * 8 4-methyl-6-methylthio- 3-pyridyl 1355 ib (id). S S * 9 4-methyl-6-methylthio- 3-pyridyl 1356 ib (id). S S * 14 4-methyl-6-methylthio- 3-pyridyl *Single Bond

TABLE 74 Com- pound No.

X Y Z n Het 1357

NH S * 1 4-meethyl-6-methylthio- 3-pyridyl 1358 ib (id). NH S * 2 4-methyl-6-methylthio- 3-pyridyl 1359 ib (id). NH S * 3 4-methyl-6-methylthio- 3-pyridyl 1360 ib (id). NH S * 4 4-methyl-6-methylthio- 3-pyridyl 1361 ib (id). NH S * 5 4-methyl-6-methylthio- 3-pyridyl 1362 ib (id). NH S * 6 4-methyl-6-methylthio- 3-pyridyl 1363 ib (id). NH S * 7 4-methyl-6-methylthio- 3-pyridyl 1364 ib (id). NH S * 8 4-methyl-6-methylthio- 3-pyridyl 1365 ib (id). NH S * 9 4-methyl-6-methylthio- 3-pyridyl 1366 ib (id). NH S * 14 4-methyl-6-methylthio- 3-pyridyl 1367 ib (id). O S * 1 5-methylthio-2-pyridyl 1368 ib (id). O S * 2 5-methylthio-2-pyridyl 1369 ib (id). O S * 3 5-methylthio-2-pyridyl 1370 ib (id). O S * 4 5-methylthio-2-pyridyl 1371 ib (id). O S * 5 5-methylthio-2-pyridyl 1372 ib (id). O S * 6 5-methylthio-2-pyridyl 1373 ib (id). O S * 7 5-methylthio-2-pyridyl 1374 ib (id). O S * 8 5-methylthio-2-pyridyl 1375 ib (id). O S * 9 5-methylthio-2-pyridyl 1376 ib (id). O S * 14 5-methylthio-2-pyridyl *Single Bond

TABLE 75 Com- pound No.

X Y Z n Het 1377

S S * 1 5-methylthio-2-pyridyl 1378 ib (id). S S * 2 5-methylthio-2-pyridyl 1379 ib (id). S S * 3 5-methylthio-2-pyridyl 1380 ib (id). S S * 4 5-methylthio-2-pyridyl 1381 ib (id). S S * 5 5-methylthio-2-pyridyl 1382 ib (id). S S * 6 5-methylthio-2-pyridyl 1383 ib (id). S S * 7 5-methylthio-2-pyridyl 1384 ib (id). S S * 8 5-methylthio-2-pyridyl 1385 ib (id). S S * 9 5-methylthio-2-pyridyl 1386 ib (id). S S * 14 5-methylthio-2-pyridyl 1387 ib (id). NH S * 1 5-methylthio-2-pyridyl 1388 ib (id). NH S * 2 5-methylthio-2-pyridyl 1389 ib (id). NH S * 3 5-methylthio-2-pyridyl 1390 ib (id). NH S * 4 5-methylthio-2-pyridyl 1391 ib (id). NH S * 5 5-methylthio-2-pyridyl 1392 ib (id). NH S * 6 5-methylthio-2-pyridyl 1393 ib (id). NH S * 7 5-methylthio-2-pyridyl 1394 ib (id). NH S * 8 5-methylthio-2-pyridyl 1395 ib (id). NH S * 9 5-methylthio-2-pyridyl 1396 ib (id). NH S * 14 5-methylthio-2-pyridyl *Single Bond

TABLE 76 Com- pound No.

X Y Z n Het 1397

O S * 1 2,4,6-trismethylthio-5- pyrimidyl 1398 ib (id). O S * 2 2,4,6-trismethylthio-5- pyrimidyl 1399 ib (id). O S * 3 2,4,6-trismethylthio-5- pyrimidyl 1400 ib (id). O S * 4 2,4,6-trismethylthio-5- pyrimidyl 1401 ib (id). O S * 5 2,4,6-trismethylthio-5- pyrimidyl 1402 ib (id). O S * 6 2,4,6-trismethylthio-5- pyrimidyl 1403 ib (id). O S * 7 2,4,6-trismethylthio-5- pyrimidyl 1404 ib (id). O S * 8 2,4,6-trismethylthio-5- pyrimidyl 1405 ib (id). O S * 9 2,4,6-trismethylthio-5- pyrimidyl 1406 ib (id). O S * 14 2,4,6-trismethylthio-5- pyrimidyl 1407 ib (id). S S * 1 2,4,6-trismethylthio-5- pyrimidyl 1408 ib (id). S S * 2 2,4,6-trismethylthio-5- pyrimidyl 1409 ib (id). S S * 3 2,4,6-trismethylthio-5- pyrimidyl 1410 ib (id). S S * 4 2,4,6-trismethylthio-5- pyrimidyl 1411 ib (id). S S * 5 2,4,6-trismethylthio-5- pyrimidyl 1412 ib (id). S S * 6 2,4,6-trismethylthio-5- pyrimidyl 1413 ib (id). S S * 7 2,4,6-trismethylthio-5- pyrimidyl 1414 ib (id). S S * 8 2,4,6-trismethylthio-5- pyrimidyl 1415 ib (id). S S * 9 2,4,6-trismethylthio-5- pyrimidyl 1416 ib (id). S S * 14 2,4,6-trismethylthio-5- pyrimidyl *Single Bond

TABLE 77 Com- pound No.

X Y Z n Het 1417

NH S * 1 2,4,6-trismethylthio-5- pyrimidyl 1418 ib (id). NH S * 2 2,4,6-trismethylthio-5- pyrimidyl 1419 ib (id). NH S * 3 2,4,6-trismethylthio-5- pyrimidyl 1420 ib (id). NH S * 4 2,4,6-trismethylthio-5- pyrimidyl 1421 ib (id). NH S * 5 2,4,6-trismethylthio-5- pyrimidyl 1422 ib (id). NH S * 6 2,4,6-trismethylthio-5- pyrimidyl 1423 ib (id). NH S * 7 2,4,6-trismethylthio-5- pyrimidyl 1424 ib (id). NH S * 8 2,4,6-trismethylthio-5- pyrimidyl 1425 ib (id). NH S * 9 2,4,6-trismethylthio-5- pyrimidyl 1426 ib (id). NH S * 14 2,4,6-trismethylthio-5- pyrimidyl *Single Bond

TABLE 78 Compound No.

X Y Z n Het 1427

O S Single Bond 1

1428

O S Single Bond 1

The compounds represented by the formula (I) in the present invention has an ACAT inhibitory activity and/or an intracellular cholesterol transfer inhibitory activity, and is useful in the medical field as medications for treating hyperlipemia or arteriosclerosis. Especially, the compounds of the present invention exhibit an activity of selectively inhibiting an ACAT enzyme which is present in the blood vessel wall. Accordingly, it is expected to have a less side effect than a non-selective ACAT inhibitor, and is preferable as an active ingredient of a drug.

The pharmaceutical composition of the present invention contains the compounds represented by the formula (I) or acid addition salts or solvates thereof as active ingredients. It comprises at least one type of the active ingredients in a therapeutically effective amount, and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention contains the compounds represented by the formula (I), or the acid addition salts or the solvates thereof as active ingredients. At least one type of the active ingredients is used singly, or can be shaped into an administrable preparation such as a tablet, a capsule, a granule, a powder, an injection or a suppository using a pharmaceutically acceptable carrier well-known to those skilled in the art, such as a excipient, a binder, a support or a diluent. These preparations can be produced by a known method. For example, an orally administrable preparation can be produced by mixing the compound represented by the formula (I) with an excipient such as starch, mannitol or lactose, a binder such as carboxymethylcellulose sodium or hydroxypropyl cellulose, a disintegrant such as crystalline cellulose or carboxymethyl cellulose calcium, a lubricant such as talc or magnesium stearate, and a fluidity improving agent such as light silicic anhydride, which are combined as required.

The pharmaceutical composition of the present invention can be administered either orally or parenterally.

The dose of the pharmaceutical composition of the present invention varies depending on the weight, the age, the sex, the progression of disease and the like of patients. Generally, it is preferably administered to an adult person at a dose of from 1 to 100 mg, preferably from 5 to 200 mg a day, from one to three times a day.

The ACAT inhibitory activity of the compounds represented by the formula (I) in the present invention was tested in the following Experiment Examples.

EXPERIMENT EXAMPLE 1 ACAT Inhibitory Activity

A microsome was prepared from the breast aorta of a rabbit which had been fed with 1% cholesterol food for 8 weeks in a usual manner, and suspended in a 0.15 M phosphate buffer solution (pH 7.4) to form an enzyme solution. An enzyme solution derived from the small intestine was prepared from the small intestine of a rabbit that had eaten a normal food.

The ACAT inhibitory activity was measured by modifying the method of J. G. Heider (J. Lipid Res., 24, 1127-1134, 1983). That is, 2 μl of a test compound dissolved in dimethyl sulfoxide (DMSO) were added to 88 μl of a 0.15 M phosphate buffer solution (pH 7.4)containing ¹⁴C-Oleoyl-CoA (40 μM, 60,000 dpm) and bovine serum albumin (2.4 mg/ml), and the mixture was incubated at 37° C. for 5 minutes.

To this solution were added 10 μl of the enzyme solution, and the mixture was reacted at 37° C. for 5 minutes (for 3 minutes in the case of the small intestine). Then, 3 ml of a chloroform/methanol (2/1) mixture and 0.5 ml of 0.04 N hydrochloric acid were added thereto to stop the reaction. The lipid was then extracted. The solvent layer was concentrated to dryness, and dissolved in hexane. The solution was spotted on a TLC plate(supplied by Merck Co.). The elution was conducted with a hexane:ether:acetic acid (75:25:1) mixture.

The radioactivity of the resulting cholesterol ester fraction was measured using BAS 2000 (supplied by Fuji Photo Film Co., Ltd.). An IC₅₀ value was obtained from the calculation in contrast with a control containing only DMSO. The results are shown in Table 79. TABLE 79 Test Compound Enzyme from A‡ Enzyme from B‡ IC₅₀ (B‡)/ No. IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (A‡) 795 0.028 0.016 0.6 811 0.014 0.38 27.1 815 0.014 0.017 1.2 818 0.0056 0.016 2.9 831 0.63 0.61 1.0 Control 1 0.45 0.87 1.9 Control 2 0.047 0.13 2.8 Control 3 0.034 0.056 1.7 Control 4 0.026 0.037 1.4 Control 5 0.01 0.065 6.5 Control 6 0.11 0.51 4.6 A‡: the blood vessel wall B‡: the small intestine

EXPERIMENT EXAMPLE 2

(ACAT Inhibitory Activity (Anti-foamation Activity) in J744 Cells and HepG2 Cells)

J774 cells or HepG2 cells were spread on a 24-well plate. The cells were incubated in a 5% CO₂ incubator at 37° C. for 24 hours using DMEM in the case of the J774 cells and a MEM culture solution in the case of the HepG2 cells (both containing 10% fetal calf serum).

The medium was replaced with 0.5 ml of each culture solution containing 10 μg/ml of 25-OH cholesterol and a test piece, and the cells were further incubated for 18 hours.

The medium was removed, and the residue was washed twice with PBS, then extracted with 1.5 ml of a hexane:isopropanol (3:2) mixture, and concentrated to dryness. The extract was dissolved in 0.2 ml of isopropanol containing 10% Triton X-100. Total cholesterol (TC) and free cholesterol (FC) were measured using Cholesterol E Test Wako (supplied by Wako Pure Chemical Industries, Ltd.) and Free Cholesterol E Test Wako (supplied by Wako Pure Chemical Industries, Ltd.).

The cell extract residue was solubilized in 0.25 ml of 2N NaOH at 37° C. for 30 minutes, and the protein amount was measured using BCA Protein Assay Reagent (Pierce).

The amount of cholesterol based on the protein was calculated from the difference between TC and FC, and an IC₅₀ value was obtained from the calculation in contrast with the control. The results are shown in Table 80. TABLE 80 Test Compound Enzyme (J774) Enzyme (HepG2) IC₅₀ (HepG2)/ No. IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (J774)  795 0.050 0.35 7.0  797 0.0036 0.029 8.1  811 0.050 1.8 36.0  815 0.12 2.6 21.7  818 0.062 0.063 1.0  831 0.057 5.4 94.7 1253 0.0041 0.0044 1.1 1282 0.0032 0.0062 1.9 1292 0.0027 0.030 11.1 1294 0.0042 0.0024 0.6 1302 0.0021 0.015 7.1 Control 1 0.56 5.3 9.5 Control 2 0.58 1.1 1.9 Control 3 0.32 1.3 4.3 Control 4 0.12 0.75 6.3 Control 5 1.9 1.6 0.8 Control 6 0.28 9.1 32.8

As control compounds, the following control compounds (1) to (6) were subjected to the same test, and the results are also shown in Tables 64 and 65. Control Compounds (1) to (6) are as follows.

Control Compound (1):

5-[2-(2-(4-fluorophenyl)ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxy-2,2-dimethyl-N-(2,6-diisopropylphenyl)pentanamide (WO 92/09582)

Control Compound (2):

(+)-(S)-2-[5-(3,5-dimethylpyrazol-1-yl)pentasulfinyl]-4,5-diphenylimidazole (EP 523941)

Control Compound (3):

N-(2,2,5,5-tetramethyl-1,3-dioxan-4-ylcarbonyl)-β-alanine 2 (S)-[N′-(2,2-dimethylpropyl)-N′-nonylureido]-1(S)-cyclohexyl ester (EP 421441)

Control Compound (4):

[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptyl-2-benzoxazolamie (WO 93/23392)

Control Compound (5):

6-(benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (compound of Japanese Patent Application No. 88,660/1997)

Contol Compound (6):

2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropylphenyl)acetamide (compound of Japanese Patent Application No. 149,892/1997)

EXAMPLES

The present invention is illustrated more specifically by referring to the following Examples. However, the present invention is not limited to these Examples.

Example 1 Compound No. 5 in Table Production of 6-(benzoxazol-2-ylthio)-N-(2-methylthio-3-pyridyl)hexanamide

A methanol (50 ml) solution of 2-chloro-3-nitropyridine (4.30 g, 27.1 mmol) was added dropwise to a methanol (30 ml) solution of sodium thiomethoxide (2.10 g, 28.5 mmol) while being cooled with ice, and the mixed solution was stirred for 17 hours. Water was then added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crystals were recrystallized from a mixture of an ethyl acetate-hexane mixture to obtain 2.93 g (yield 64%) of 2-methylthio-3-nitropyridine as a yellow needle crystal.

This nitropyridine (851 mg, 5.0 mmol) was dissolved in a mixed solvent of acetic acid (35 ml) and conc. hydrochloric acid (1.4 ml), and zinc (3.92 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 600 mg (yield 86%) of 3-amino-2-methylthiopyridine as a pale yellow oil.

Triethylamine (520 mg, 5.14 mmol) was added to a THF (7 ml) solution of this aminopyridine (600 mg, 4.28 mmol). Subsequently, 6-bromohexanoyl chloride (1.10 g, 5.14 mmol) was slowly added dropwise thereto while being cooled with ice, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent-hexane:ethyl acetate=6:1→3:1→2:1) to obtain 1.08 g (yield 79%) of 6-bromo-N-(2-methylthio-3-pyridyl)hexanamide as a colorless needle crystal (melting point: 66 to 67° C.).

To a DMF (2 ml) solution of this amide (159 mg, 0.5 mmol) and 2-mercaptobenzoxazole (83 mg, 0.55 mmol) were added 18-crown-6 (13 mg, 0.05 mmol) and potassium carbonate (83 mg, 0.6 mmol). and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent-hexane:ethyl acetate=5:2→2:1) to obtain 156 g (yield 81%) of a desired compound as a colorless needle crystal.

Melting point:127-128° C.

IR (KBr) cm⁻¹: 3447, 3265, 1654, 1522, 1508.

¹H-NMR (CDCl₃) δ:

-   -   1.58-1.65 (2H, m), 1.83 (2H, quint, J=7.4 Hz),     -   1.92 (2H, quint, J=7.4 Hz), 2.46 (2H, t, J=7.4 Hz),     -   2.62 (3H, s), 3.34 (2H, t, J=7.4 Hz),     -   7.06 (1H, dd, J=8.1, 4.6 Hz), 7.21-7.30 (3H, m),     -   7.44 (1H, m), 7.59 (1H, m), 8.26 (1H, d, J=4.6 Hz),     -   8.28 (1H, d, J=8.1 Hz).

EIMS m/z (relative intensity): 387 (M⁺), 165 (100).

Elemental analysis: as C₁₉H₂₁N₃O₂S₂

calculated: C, 58.89; H, 5.46; N, 10.84; S, 16.55.

found: C, 58.92; H, 5.43; N, 10.78: S, 16.55.

Example 2 Compound No. 8 in Table Production of 9-(benzoxazol-2-ylthio)-N-(2-methylthio-3-pyridiyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 1 except that 9-bromononanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain 9-bromo-N-(2-methylthio-3-pyridyl)nonanamide.

To a DMF (5 ml) solution of this amide (90 mg, 0.25 mmol) and 2-mercaptobenzoxazole (38 mg, 0.25 mmol) were added potassium carbonate (42 mg, 0.30 mmol) and 18-crown-6 (7 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was recrystallized from a mixture of ethyl acetate-hexane to obtain 83 mg (yield 77%) of the desired compound as a colorless powdery crystal.

Melting point: 84-85° C.

IR (KBr) cm⁻¹: 3465, 3276, 2926, 1664, 1505.

¹H-NMR (CDCl₃) δ:

-   -   1.35-1.53 (8H, m), 1.72-1.77 (2H, m),     -   1.80-1.87 (2H, m), 2.42 (2H, t, J=7.3 Hz),     -   2.63 (3H, s), 3.31 (2H, t, J=7.4 Hz),     -   7.06 (1H, dd, J=8.0, 4.7 Hz), 7.21-7.30 (3H, m),     -   7.43 (1H, dd, J=7.0, 0.6 Hz),     -   7.59 (1H, dd, J=7.6, 0.6 Hz),     -   8.25 (1H, d, J=4.7 Hz), 8.31 (1H, d, J=7.8 Hz).

EIMS m/z (relative intensity): 429 (M⁺), 297 (100).

Elemental analysis: as C₂₂H₂₇N₃O₂S₂

calculated: C, 61.51; H, 6.33; N, 9.78; S, 14.93.

found: C, 61.51; H, 6.28; N, 9.64; S, 14.99.

Example 3 Compound No. 15 in Table Production of 6-(benzothiazol-2-ylthio)-N-(2-methylthio-3-pyridyl)hexanamide

The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 118-119° C.

IR (KBr) cm⁻¹: 3429, 3265, 1654, 1522, 1508.

¹H-NMR (CDCl₃) δ:

-   -   1.57-1.65 (2H, m), 1.83 (2H, quint, J=7.4 Hz),     -   1.91 (2H, quint, J=7.4 Hz), 2.46 (2H, t, J=7.4 Hz), 2.61 (3H,         s), 3.38 (2H, t, J=7.4 Hz),     -   7.06 (1H, dd, J=8.1, 4.9 Hz), 7.25 (1H, br s),     -   7.29 (1H, m), 7.41 (1H, m), 7.75 (1H, m), 7.86 (1H, m),     -   8.25 (1H, d, J=4.9 Hz), 8.29 (1H, d, J=8.1 Hz).

EIMS m/z (relative intensity): 403 (M⁺), 223 (100).

Elemental analysis: as C₁₉H₂₁N₃OS₃

calculated: C, 56.55; H, 5.24; N, 10.41; S, 23.83.

found: C, 56.69; H. 5.30; N, 10.24; S, 23.77.

Example 4 Compound No. 18 in Table Production of 9-(benzothiazol-2-ylthio)-N-(2-methylthio-3-pyridyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 2 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 107-108° C.

IR (KBr) cm⁻¹: 3448, 3256, 2923, 1656, 1525.

¹H-NMR (d6-DMSO) δ:

-   -   1.24-1.34 (6H, m), 1.36-1.43 (2H, m),     -   1.54-1.59 (2H, m), 1.69-1.77 (2H, m),     -   2.26 (2H, t, J=7.4 Hz), 2.40 (3H, s),     -   3.28 (2H, t, J=7.2 Hz),     -   7.01 (1H, dd, J=7.8, 4.6 Hz),     -   7.26 (1H, dt, J=8.1, 1.2 Hz),     -   7.36 (1H, dt, J=7.3, 1.2 Hz),     -   7.58 (1H, dd, J=7.8, 1.5 Hz),     -   7.74 (1H, d, J=8.1 Hz),     -   7.85 (1H, dd, J=7.3 , 1.2 Hz),     -   8.21 (1H, dd, J=4.6 , 1.5 Hz), 8.73 (1H, br s).

EIMS m/z (relative intensity): 445 (M⁺), 297 (100).

Elemental analysis: as C₂₂H₂₇N₃OS₃

calculated: C, 59.29; H, 6.11: N, 9.43; S, 21.58.

found: C, 59.12; H, 6.02: N, 9.25; S, 21.62.

Example 5 Compound No. 25 in Table Production of 6-(benzimidazol-2-ylthio)-N-(2-methylthio-3-pyridyl)hexanamide

The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow needle crystal.

Melting point: 121-123° C.

IR (KBr) cm⁻¹: 3386, 3276, 1658, 1511, 1398.

¹H-NMR (CDCl₃) δ:

-   -   1.52-1.60 (2H, m), 1.74-1.86 (4H, m),     -   2.42 (2H, t, J=7.2 Hz), 2.60 (3H, s),     -   3.32 (2H, t, J=7.2 Hz), 7.05 (1H, dd, J=8.1, 4.9 Hz),     -   7.18-7.19 (2H, m), 7.32 (1H, br s), 7.36 (1H, br s), 7.66 (1H,         br s), 8.23-8.26 (2H, m), 9.84 (1H, br s).

EIMS m/z (relative intensity): 386 (M⁺), 205 (100).

Elemental analysis: as C₁₉H₂₂N₄OS₂

calculated: C, 59.04; H, 5.74: N, 14.49; S, 16.59.

found: C, 59.06; H, 5.76: N, 14.35; S, 16.57.

Example 6 Compound No. 28 in Table Production of 9-(benzimidazol-2-ylthio)-N-(2-methylthio-3-pyridyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 2 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

IR (KBr) cm⁻¹: 3260, 2929, 2851, 1664, 1519, 1394.

¹H-NMR (CDCl₃) δ:

-   -   1.31-1.47 (6H, m), 1.57-1.61 (2H, m),     -   1.69-1.79 (4H, m), 2.42 (2H, t, J=7.2 Hz),     -   2.63 (3H, s), 3.32 (2H, t, J=7.4 Hz),     -   7.06 (1H, dd, J=8.1 , 4.6 Hz), 7.18-7.23 (4H, m), 7.67 (1H, br         s),8.26 (1H, d, J=4.6 Hz),     -   8.30 (1H, d, J=7.8 Hz), 9.31 (1H, br s).

EIMS m/z (relative intensity): 428 (M⁺), 164 (100).

Example 7 Compound No. 158 in Table Production of 9-(benzoxazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-chloro-4-methyl-3-nitropyridine was used instead of 2-chloro-3-nitropyridine to obtain 4-methyl-2-methylthio-3-nitropyridine. This nitropyridine (474 mg, 2.57 mmol) was dissolved in a mixed solvent of acetic acid (18 ml) and conc. hydrochloric acid (0.7 ml), and zinc (2.02 g, 30.88 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 307 mg (yield 77%) of 3-amino-4-methyl-2-methylthiopyridine as a colorless crystal.

Triethylamine (302 mg, 2.99 mmol) was added to a chloroform (4 ml) solution of this aminopyridine (307 mg, 1.99 mmol), and a chloroform (4 ml) solution of 9-bromononanyl chloride (2.99 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 125 g, eluent-hexane:ethyl acetate=3:1→2:1) to obtain 261 mg (yield 35%) of 9-bromo-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless powdery crystal (melting point: 77 to 78° C.). To a DMF (5 ml) solution of this amide (114 mg, 0.31 mmol) and 2-mercaptobenzoxazole (46 mg, 0.31 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (51 mg, 0.37 mmol), and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—chloroform:methanol=20:1) to obtain 89 mg (yield 66%) of the desired compound as a colorless powdery crystal.

Melting point: 91-92° C.

IR (KBr) cm⁻¹: 3433, 3268, 2924, 1518, 1496.

¹H-NMR (CDCl₃) δ:

-   -   1.36-1.53 (8H, m), 1.74-1.88 (4H, m), 2.21 (3H, s),     -   2.43 (2H, t, J=7.6 Hz), 2.53 (3H, s),     -   3.32 (2H, t, J=7.3 Hz), 6.63 (1H, br s),     -   6.90 (1H, d, J=5.1 Hz), 7.22-7.30 (1H, m),     -   7.43 (1H, dd, J=7.2 , 1.4 Hz),     -   7.60 (1H, dd, J=7.6 , 1.4 Hz),     -   8.24 (1H, d, J=4.9 Hz).

EIMS m/z (relative intensity): 443 (M⁺, 100).

Elemental analysis: as C₂₃H₂₉N₃O₂S₂

calculated: C, 62.27; H, 6.59: N, 9.47; S, 14.45.

found: C, 62.34; H, 6.58: N, 9.33; S, 14.44.

Example 8 Compound No. 168 in Table Production of 9-(benzothiazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 7 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 88-90° C.

IR (KBr) cm⁻¹: 3449, 3271, 2925, 1657, 1425, 997.

¹H-NMR (CDCl₃) δ:

-   -   1.37-1.53 (8H, m), 1.73-1.87 (4H, m), 2.21 (3H, s),     -   2.43 (2H, t, J=7.6 Hz), 2.53 (3H, s),     -   3.35 (2H, t, J=7.3 Hz), 6.62 (1H, br s),     -   6.90 (1H, d, J=5.1 Hz), 7.23-7.31 (1H, m),     -   7.39-7.43 (1H, m), 7.75 (1H, dd, J=8.1, 0.5 Hz),     -   7.86 (1H, dd, J=8.1, 0.5 Hz),     -   8.24 (1H, d, J=5.1 Hz).

Elemental analysis: as C₂₃H₂₉N₃OS₃

calculated: C, 60.10; H, 6.36: N, 9.14.

found: C, 59.99; H, 6.36: N, 9.00.

Example 9 Compound No. 275 in Table Production of 6-(benzoxazol-2-ylthio)-N-[2,6-bis(methylthio)-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 1 except that 2,6-dichloro-3-nitropyridine was used instead of 2-chloro-3-nitropyridine. This nitropyridine (800 mg, 3.70 mmol) was dissolved in a mixed solvent of acetic acid (100 ml) and conc. hydrochloric acid (5.6 ml), and zinc (2.90 g, 44.39 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent:hexane:ethyl acetate=4:1) to obtain 301 mg (yield 44%) of 3-amino-2,6-bis(methylthio)pyridine as a pale yellow powdery crystal.

Triethylamine (196 mg, 1.94 mmol) was added to a THF (3 ml) solution of this aminopyridine (301 mg, 1.62 mmol), and a THF (1 ml) solution of 6-bromohexanoyl chloride (345 mg, 1.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=4:1) to obtain 453 mg (yield 77%) of 6-bromo-N-[2,6-bis(methylthio)-3-pyridyl]hexanamide as a colorless powdery crystal (melting point: 117 to 119° C.). To a DMF (4 ml) solution of this amide (100 mg, 0.28 mmol) and 2-mercaptobenzoxazole (42 mg, 0.28 mmol) were added 18-crown-6 (7 mg, 0.03 mmol) and potassium carbonate (46 mg, 0.33 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 83 mg (yield 70%) of the desired compound as a colorless powdery crystal.

Melting point: 125-126° C.

IR (KBr) cm⁻¹: 3436, 3253, 2937, 1653, 1519, 1505.

¹H-NMR (CDCl₃) δ:

-   -   1.57-1.65 (2H, m), 1.78-1.86 (2H, m),     -   1.88-1.95 (2H, m), 2.44 (2H, t, J=7.4 Hz),     -   2.57 (3H, s), 2.62 (3H, s), 3.33 (2H, t, J=7.3 Hz),     -   6.93 (1H, d, J=8.4 Hz),7.02 (1H, br s),     -   7.21-7.30 (29, m), 7.43 (1H, dd, J=7.4 , 1.7 Hz),     -   7.59 (1H, dd, J=7.4, 1.7 Hz),     -   8.01 (1H, d, J=8.4 Hz),

Elemental analysis: as C₂₀H₂₃N₃O₂S₃

calculated: C, 55.40; H, 5.35: N, 9.69.

found: C, 55.53; H, 5.38: N, 9.68.

Example 10 Compound No. 455 in Table Production of 6-(benzoxazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide

The reaction and the treatment were conducted in the same manner as in Example 1 except that 2-chloro-6-methyl-3-nitropyridine was used instead of 2-chloro-3-nitropyridine to obtain 6-methyl-2-methylthio-3-nitropyridine. This nitropyridine (921 mg, 5.0 mmol) was dissolved in a mixed solvent of acetic acid (40 ml) and conc. hydrochloric acid (1.75 ml), and zinc (3.81 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 30 minutes, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 685 mg (yield 88%) of 3-amino-6-methyl-2-methylthiopyridine as a yellow oil.

Triethylamine (475 mg, 4.7 mmol) was added to a chloroform (10 ml) solution of this aminopyridine (601 mg, 3.9 mmol), and 6-bromohexanoyl chloride (944 mg, 4.29 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 50 g, eluent—hexane:ethyl acetate=10:1→5:1) to obtain 773 mg (yield 59%) of 6-bromo-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide as a colorless crystal (melting point: 98 to 99° C.). To a DMF (2 ml) solution of this amide (133 mg, 0.4 mmol) and 2-mercaptobenzoxazole (67 mg, 0.44 mmol) were added 18-crown-6 (11 mg, 0.04 mmol) and potassium carbonate (67 mg, 0.44 mmol), and the mixture was stirred at 80° C. for 90 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent-hexane:acetone=5:1→5:3) to obtain 125 mg (yield 78%) of the desired compound as a colorless needle crystal.

Melting point: 140-141° C.

IR (KBr) cm⁻¹: 3437, 3267, 1654, 1528, 1506.

¹H-NMR (CDCl₃) δ:

-   -   1.57-1.65 (2H, m),. 1.82 (2H, quint, J=7.4 Hz),     -   1.91 (2H, quint, J=7.4 Hz), 2.44 (2H, t, J=7.4 Hz),     -   2.48 (3H, s), 2.60 (3H, s), 3.33 (2H, t, J=7.4 Hz),     -   6.90 (1H, d, J=8.1 Hz), 7.21-7.30 (2H, m),     -   7.43 (1H, m), 7.59 (1H, m), 8.13 (1H, d, J=8.1 Hz).

EIMS m/z (relative intensity): 401 (M⁺), 203 (100).

Elemental analysis: as C₂₀H₂₃N₃O₂S₂

calculated: C, 59.82; H, 5.77: N, 10.46.

found: C, 59.90; H, 5.84: N, 10.32.

Example 11 Compound No. 458 in Table Production of 9-(benzoxazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide

Triethylamine (607 mg, 6.0 mmol) was added to a chloroform (10 ml) solution of 3-amino-6-methyl-2-methylthiopyridine (685 mg, 4.44 mmol), and a chloroform (3 ml) solution of 9-bromononanyl chloride (1,281 mg, 5 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent—hexane:ethyl acetate=10:1→4:1) to obtain 433 mg (yield 27%) of 9-bromo-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide as a colorless crystal (melting point: 80 to 82° C.).

To a DMF (1.5 ml) solution of this amide (131 mg, 0.35 mmol) and 2-mercaptobenzoxazole (58 mg, 0.385 mmol) were added 18-crown-6 (,9 mg, 0.035 mmol) and potassium carbonate (58 mg, 0.42 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 30 g, eluent—hexane:ethyl acetate=4:1→3:1) to obtain 123 mg (yield 79%) of the desired compound as a colorless needle crystal.

Melting point: 99-100° C.

IR (KBr) cm⁻¹: 3421, 3235, 2924, 1655, 1528, 1497, 1455.

¹H-NMR (CDCl₃) δ:

-   -   1.32-1.42 (6H, m), 1.43-1.51 (2H, m), 1.70-1.78 (2H, m),     -   1.83 (2H, quint, J=-7.4 Hz), 2.40 (2H, t, J=7.4 Hz),     -   2.48 (3H, s), 2.61 (3H, s), 3.31 (2H, t, J=7.4 Hz),     -   6.90 (1H, d, J=8.1 Hz), 7.21-7.30 (3H, m),     -   7.43 (1H, m), 7.60 (1H, m), 8.15 (1H, d, J=8.1 Hz).

EIMS m/z (relative intensity): 443 (M⁺), 311 (100).

Example 12 Compound No. 465 in Table Production of 6-(benzothiazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide

The reaction and the treatment were conducted in the same manner as in Example 10 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 122-123° C.

IR (KBr) cm⁻¹: 3438, 3290, 1656, 1515, 1431.

¹H-NMR (CDCl₃) δ:

-   -   1.57-1.65 (2H, m), 1.82 (2H, quint, J=7.4 Hz),     -   1.90 (2H, quint, J=7.4 Hz), 2.44 (2H, t, J=7.4 Hz),     -   2.48 (3H, s), 2.60 (3H, s), 3.37 (2H, t, J=7.4 Hz),     -   6.90 (1H, d, J=8.3 Hz), 7.22(1H, br s) 7.29 (1H, m),     -   7.41 (1H, m), 7.75 (1H, m), 7.86 (1H, m),     -   8.13 (1H, J=8.3 Hz).

EIMS m/z (relative intensity): 417 (M⁺), 168 (100).

Elemental analysis: as C₂₀H₂₃N₃OS₃

calculated: C, 57.52; H, 5.55: N, 10.06.

found: C, 57.65; H, 5.63: N, 9.97.

Example 13 Compound No. 468 in Table Production of 9-(benzothiazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 11 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 104-105° C.

IR (KBr) cm⁻¹: 3280, 2924, 1662, 1527, 1428.

¹H-NMR (CDCl₃) δ:

-   -   1.32-1.41 (6H, m), 1.43-1.51 (2H, m), 1.70-1.77 (2H, m),     -   1.82 (2H, quint, J=7.4 Hz), 2.40 (2H, t, J 7.4 Hz),     -   2.48 (3H, s), 2.61 (3H, s), 3.34 (2H, t, J=7.4 Hz),     -   6.90 (1H, d, J=8.1 Hz), 7.22 (1H, br s) 7.29 (1H, m),     -   7.41 (1H, m), 7.76 (1H, m), 7.86 (1H, m),     -   8.15 (1H, d, J=8.1 Hz),

EIMS m/z (relative intensity): 459 (M⁺), 293 (100).

Elemental analysis: as C₂₃H₂₉N₃OS₃

calculated: C, 60.10; H, 6.36: N, 9.14.

found: C, 60.17; H, 6.40: N, 9.11.

Example 14 Compound No. 475 in Table Production of 6-(benzimidazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl )hexanamide

The reaction and the treatment were conducted in the same manner as in Example 10 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 138-140° C.

IR (KBr) cm⁻¹: 3385, 3244, 1668, 1509, 1440.

¹H-NMR (CDCl₃) δ:

-   -   1.53-1.61 (2H, m), 1.78 (2H, quint, J=7.6 Hz),     -   1.82 (2H, quint, J=7.6 Hz), 2.41 (2H, t, J=7.6 Hz),     -   2.48 (3H, s), 2.59 (3H, s), 3.31 (2H, t, J=7.6 Hz),     -   6.88 (1H, d, J 8.3 Hz), 7.16-7.23 (2H, m),     -   7.31-7.32 (2H, m), 7.67 (1H, m),     -   8.08 (1H, d, J=8.3 Hz), 9.72 (1H, br s).

EIMS m/z (relative intensity): 400 (M⁺), 164 (100).

Elemental analysis: as C₂₀H₂₄N₄OS₂

calculated: C, 59.97; H, 6.04: N, 13.99.

found: C, 60.08; H, 6.08: N, 13.94.

Example 15 Compound No. 478 in Table Production of 9-(benzimidazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)nonanamide

The reaction and the treatment were conducted in the same manner as in Example 11 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 73-75° C.

IR (KBr) cm⁻¹: 3254, 2926, 1663, 1515, 1438.

¹H-NMR (CDCl₃) δ:

-   -   1.27-1.43 (8H, m), 1.68-1.78 (4H, m),     -   2.40 (2H, t, J=7.4 Hz), 2.48 (3H, s), 2.60 (3H, s),     -   3.31 (2H, t, J=7.4 Hz), 6.89 (1H, d, J=8.1 Hz),     -   7.17-7.20 (2H, m), 7.31-7.33 (2H, m), 7.67 (1H, m),     -   8.13 (1H, d, J=8.1 Hz), 9.69 (1H, br s).

Example 16 Compound No. 781 in Table Production of 2-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide

Triethylamine (274 mg, 2.71 mmol) was added to a chloroform (10 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (492 mg, 2.46 mmol), and bromoacetyl bromide (521 mg, 2.58 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with methylene chloride. The organic layer was washed with 1N hydrochloric acid, water, an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride in this order, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 25 g, eluent—hexane:acetone=7:1→5:1→3:1) to obtain 100 mg (yield 13%) of 2-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide as a colorless crystal (melting point: 171 to 172° C.).

Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (5 ml) solution of this amide (96 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 10 g, eluent—hexane:acetone=5:2) to obtain 88 mg (yield 75%) of the desired compound as a colorless crystal.

Melting point: 203-205° C.

IR (KBr) cm⁻¹: 3437, 3238, 1669, 1509, 1454.

¹H-NMR (CDCl₃) δ:

-   -   2.31 (3H, s), 2.41 (3H, s), 2.46 (3H, s), 4.10 (2H, s),     -   6.61 (1H, s), 7.28-7.33 (2H, m), 7.49 (1H, m),     -   7.60 (1H, m), 8.77 (1H, br s).

EIMS m/z (relative intensity): 391 (M⁺), 227 (100).

Elemental analysis: as C₁₇H₁₇N₃O₂S₃

calculated: C, 52.15; H, 4.38; N, 10.73.

found: C, 52.14; H, 4.44; N, 10.57.

Example 17 Compound No. 783 in Table Production of 4-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide

Triethylamine (206 mg, 2.04 mmol) was added to a THF (6 ml) solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (341 mg, 1.70 mmol), and 4-bromobutanoyl chloride (379 mg, 2.04 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 75 g, eluent—hexane:acetone=5:1→3:1) to obtain 390 mg (yield 66%) of 4-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide as a colorless crystal (melting point: 139 to 140° C.).

To a DMF (2 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (50 mg, 0.33 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (50 mg, 0.36 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:2, eluted twice) to obtain 67 mg (yield 53%) of the desired compound as a colorless needle crystal.

Melting point: 149-150° C.

IR (KBr) cm⁻¹: 3437, 3248, 1667, 1503, 1455.

¹H-NMR (d6-DMSO) δ:

-   -   2.13 (2H, quint, J=7.2 Hz), 2.37 (3H, s),     -   2.38 (3H, s), 2.44 (3H, s), 2.49 (2H, t, J=7.2 Hz),     -   3.43 (2H, t, J=7.2 Hz), 6.88 (1H, s),     -   7.30-7.37 (2H, m), 7.64-7.68 (2H, m),     -   9.45 (1H, br s).

EIMS m/z (relative intensity): 419 (M⁺, 100).

Elemental analysis: as C₁₉H₂₁N₃O₂S₃

calculated: C, 54.39; H, 5.04; N, 10.01.

found: C, 54.58; H, 5.08; N, 9.98.

Example 18 Compound No. 785 in Table Production of 6-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 6-bromohexanoyl chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless powdery crystal.

Melting point: 120-121° C.

IR (KBr) cm⁻¹: 3433, 3235, 1662, 1502, 1455.

¹H-NMR (d6-DMSO) δ:

-   -   1.44-1.54 (2H, m), 1.58-1.68 (2H, m),     -   1.72-1.82 (2H, m), 2.18-2.27 (2H, m), 2.32 (3H, s),     -   2.34 (3H, s), 2.37 (3H, s), 3.27 (2H, t, J=7.2 Hz),     -   6.78 (1H, s), 7.19-7.26 (2H, m),     -   7.47-7.53 (2H, m), 8.74 (1H, br s).

EIMS m/z (relative intensity): 446 (M⁺−1), 200 (100).

Elemental analysis: as C₂₁H₂₅N₃O₂S₃

calculated: C, 56.35; H, 5.63: N, 9.39; S, 21.49.

found: C, 56.42; H, 5.62: N, 9.26; S, 21.39.

Example 19 Compound No. 788 in Table Production of 9-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 9-bromononanoyl chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless powdery crystal.

Melting point: 123-124° C.

IR (KBr) cm⁻¹: 3461, 3246, 1671, 1504, 1454.

¹H-NMR (d6-DMSO) δ:

-   -   1.26-1.46 (8H, m), 1.53-1.63 (2H, m),     -   1.72-1.83 (2H, m), 2.24 (2H, t, J=7.3 Hz),     -   2.37 (3H, s), 2.38 (3H, s), 2.43 (3H, s),     -   3.31-3.41 (2H, m), 6.86 (1H, s), 7.27-7.34 (2H, m),     -   7.58-7.66 (2H, m), 9.26 (1H, br s).

EIMS m/z (relative intensity): 489 (M⁺, 100).

Elemental analysis: as C₂₄H₃₁N₃O₂S₃

calculated: C, 58.86; H, 6.38: N, 8.58; S, 19.64.

found: C, 58.94; H, 6.37: N, 8.44; S, 19.55.

Example 20 Compound No. 793 in Table Production of 4-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 131-133° C.

IR (KBr) cm⁻¹: 3435, 3250, 1665, 1509, 1428.

¹H-NMR (d6-DMSO) δ:

-   -   2.11 (2H, quint, J=7.2 Hz), 2.37 (3H, s),     -   2.38 (3H, s), 2.44 (3H, s), 2.49 (2H, t, J=7.2 Hz),     -   3.46 (2H, t, J=7.2 Hz), 6.88 (1H, s),     -   7.37 (1H, m), 7.47 (1H, m), 7.87 (1H, m), 8.02 (1H, m),     -   9.45 (1H, s).

EIMS m/z (relative intensity): 435 (M⁺), 168 (100).

Elemental analysis: as C₁₉H₂₁N₃OS₄

calculated: C, 52.39; H, 4.86: N, 9.65.

found: C, 52.39; H, 4.84:.N, 9.56.

Example 21 Compound No. 795 in Table Production of 6-(benzothiazol-2-ylthio)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 18 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow crystal.

Melting point: 123-125° C.

IR (KBr) cm⁻¹: 3433, 3258, 2923, 1661, 1429

¹H-NMR (d6-DMSO) δ:

-   -   1.49-1.58 (6H, m), 1.67 (2H, quint, J=7.2 Hz),     -   1.83 (2H, quint, J=7.2 Hz), 2.29 (2H, t, J=7.2 Hz),     -   2.38 (3H, s), 2.39 (3H, s), 2.45 (3H, s),     -   3.38 (2H, t, J=7.2 Hz), 6.68 (1H, s),     -   7.36 (1H, td, J=8.0, 1.0 Hz),     -   7.46 (1H, td, J=8.0, 1.0 Hz),     -   7.86 (1H, dd, J=8.0, 1.0 Hz),     -   8.01 (1H, br d, J=8.0 Hz), 9.31 (1H, s).

EIMS m/z (relative intensity): 463 (M⁺), 201 (100).

Elemental analysis: as C₂₁H₂₅N₃OS₄

calculated: C, 54.40; H, 5.43: N, 9.06; S, 27.66.

found: C, 54.42; H, 5.45: N, 8.79; S, 27.68.

Example 22 Compound No. 798 in Table Production of 9-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 19 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 126-127° C.

IR (KBr) cm⁻: 3440, 3252, 2924, 1661, 1430.

¹H-NMR (d6-DMSO) δ:

-   -   1.31-1.52 (8H, m), 1.59-1.68 (2H, m),     -   1.77-1.85 (2H, m), 2.23-2.33 (2H, m), 2.40 (3H, s),     -   2.42 (3H, s), 2.45 (3H, s), 3.36 (2H, t, J=7.2 Hz),     -   6.86 (1H, s), 7.34 (1H, dt, J=7.8 , 1.2 Hz),     -   7.44 (1H, dt, J=7.8 , 1.2 Hz),     -   7.83 (1H, d, J=8.3 Hz),     -   7.93 (1H, dt, J=7.8 , 0.6 Hz), 8.78 (1H, br s).

EIMS m/z (relative intensity): 504 (M⁺−1), 200 (100).

Elemental analysis: as C₂₄H₃₁N₃OS₄

calculated: C, 57.00; H, 6.18: N, 8.31; S, 25.36.

found: C, 57.08; H, 6.17: N, 8.15; S, 25.41.

Example 23 Compound No. 803 in Table Production of 4-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow needle crystal.

Melting point: 177-179° C.

IR (KBr) cm⁻¹: 3421, 3147, 1659, 1645, 1438.

¹H-NMR (d6-DMSO) δ:

-   -   2.06 (2H, quint, J=7.2 Hz), 2.38 (3H, s),     -   2.39 (3H, s), 2.44 (3H, s), 2.46 (2H, t, J=7.2 Hz),     -   3.36 (2H, t, J=7.2 Hz), 6.88 (1H, s),     -   7.09-7.13 (2H, m), 7.34-7.52 (2H, m), 9.48 (1H, s),     -   12.54 (1H, br s).

EIMS m/z (relative intensity): 418 (M⁺), 150 (100).

Example 24 Compound No. 805 in Table Production of 6-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 18 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 139-141° C.

IR (KBr) cm⁻¹: 3433, 3244, 2924, 1659, 1437.

¹H-NMR (d6-DMSO) δ:

-   -   1.47-1.56 (2H, m), 1.65 (2H, quint, J=7.2 Hz),     -   1.76 (2H, quint, J=7.2 Hz), 2.28 (2H, t, J=7.2 Hz),     -   2.38 (3H, s), 2.39 (3H, s), 2.44 (3H, s),     -   3.29 (2H, t, J=7.2 Hz), 6.68 (1H, s),     -   7.08-7.13 (2H, m), 7.36 (1H, m), 7.50 (1H, m),     -   9.30 (1H, s), 12.50 (1H, br s)

EIMS m/z (relative intensity): 446 (M⁺), 200 (100).

Example 25 Compound No. 808 in Table Production of 9-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 19 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

IR (KBr) cm⁻¹: 3146, 2925, 2854, 1660, 1523, 1437.

¹H-NMR (d6-DMSO) δ:

-   -   1.25-1.44 (8H, m), 1.53-1.61 (2H, m),     -   1.65-1.74 (2H, m), 2.24 (2H, t, J=7.3 Hz),     -   2.37 (3H, s), 2.38 (3H, s), 2.43 (3H, s),     -   3.26 (2H, t, J=7.1 Hz), 6.86 (1H, s),     -   7.07-7.12 (2H, m), 7.32-7.37 (1H, m),     -   7.46-7.54 (1H, m), 9.26 (1H, s).

EIMS m/z (relative intensity): 488 (M⁺), 150 (100).

Example 26 Compound No. 811 in Table Production of 2-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

Ethanethiol (1.55 g, 25 mmol) was added dropwise to an ethanol (50 ml) solution of sodium ethoxide (1.27 g, 25 mmol) while being cooled with ice, and the mixture was stirred for 30 minutes. While being cooled with ice, a DMF (40 ml) solution of 2,4-dichloro-6-methyl-3-nitropyridine (2.1 g, 10 mmol) was slowly added thereto dropwise. After the mixture was stirred for 2 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 2.45 g (yield 95%) of 2,4-bis(ethylthio)-6-methyl-3-nitropyridine as a yellow needle crystal.

This nitropyridine (775 mg, 3 mmol) was dissolved in a mixed solvent of acetic acid (30 ml) and conc. hydrochloric acid (1.5 ml), and zinc (4 g, 60 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 10 minutes, the reaction mixture was filtered, and the filtrate was neutralized with a sodium hydroxide aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 590 mg (yield 86%) of 3-amino-2,6-bis(ethylthio)-6-methylpyridine as a yellow oil. Triethylamine (304 mg, 3 mmol) was added to a THF (10 ml) solution of this aminopyridine (590 mg, 2.6 mmol), and bromoacetyl bromide (606 mg, 3 mmol) was then slowly added thereto dropwise while being cooled with ice. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (silica gel 60 g, eluent—hexane:acetone=10:1→5:1) to obtain 410 mg (yield 45%) of 2-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide as a light brown needle crystal. Potassium carbonate (46 mg, 0.33 mmol) was added to an acetonitrile (3 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:1) to obtain 70 mg (yield 56%) of the desired compound as a colorless needle crystal.

Melting point: 143-145° C.

IR (KBr) cm⁻¹: 3429, 3224, 1673, 1509, 1454.

¹H-NMR (CDCl₃) δ:

-   -   1.17 (3H, t, J=7.3 Hz), 1.20 (3H, t, J=7.5 Hz),     -   2.43 (3H, s), 2.81 (2H, q, J=7.3 Hz),     -   3.04 (2H, q, J=7.5 Hz), 4.11 (2H, s),     -   6.63 (1H, s), 7.25-7.33 (2H, m), 7.48 (1H, m),     -   7.61 (1H, m), 8.63 (1H, br s).

EIMS m/z (relative intensity): 419 (M⁺), 268 (100).

Elemental analysis: as C₁₉H₂₁N₃O₂S₃

calculated: C, 54.39; H, 5.04: N, 10.01.

found: C, 54.39; H, 5.05: N, 10.00.

Example 27 Compound No. 815 in Table Production of 6-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 26 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (2 ml) solution of this amide (122 mg, 0.3 mmol) and 2-mercaptobenzoxazole (45 mg, 0.3 mmol) were added potassium carbonate (46 mg, 0.33 mmol) and 18-crown-6 (8 mg, 0.03 mmol), and the mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent—hexane:acetone=5:2) to obtain 65 mg (yield 46%) of the desired compound as a light brown needle crystal.

Melting point: 100-103° C.

IR (KBr) cm⁻¹: 3233, 2928, 1668, 1504, 1455.

¹H-NMR (d6-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz),     -   1.58 (2H, m), 1.70 (2H, m), 1.85 (2H, m), 2.32 (2H, m),     -   2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz),     -   3.07 (2H, q, J=7.3 Hz), 3.35 (2H, t, J=7.3 Hz),     -   6.89 (1H, s), 7.26-7.34 (2H, m), 7.54-7.62 (2H, m),     -   8.77 (1H, br s).

EIMS m/z (relative intensity): 475 (M⁺, 100).

Elemental analysis: as C₂₃H₂₉N₃O₂S₃

calculated: C, 58.08; H, 6.14; N, 8.83; S, 20.22.

found: C, 58.07; H, 6.13; N, 8.66; S, 20.27.

Example 28 Compound No. 818 in Table Production of 9-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 9-bromononanoyl chloride was used instead of 6-bromohexanoyl bromide to obtain the desired compound as a colorless needle crystal.

Melting point: 84-87° C.

IR (KBr) cm⁻¹: 3252, 2923, 1665, 1501, 1455.

¹H-NMR (d6-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz),     -   1.28-1.52 (8H, m), 1.63 (2H, m),     -   1.82 (2H, quint, J=7.2 Hz), 2.26 (2H, m),     -   2.43 (3H, s), 2.94 (2H, q, J=7.3 Hz),     -   3.07 (2H, q, J=7.3 Hz), 3.34 (2H, t, J=7.2 Hz),     -   6.88 (1H, s), 7.26-7.34 (2H, m), 7.54-7.62 (2H, m),     -   8.72 (1H, br s).

EIMS m/z (relative intensity): 517 (M⁺), 367 (100).

Elemental analysis: as C₂₆H₃₅N₃O₂S₃

calculated: C, 60.31; H, 6.81; N, 8.12.

found: C, 60.52; H, 6.85; N, 7.85.

Example 29 Compound No. 821 in Table Production of 2-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 26 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 119-120° C.

IR (KBr) cm⁻¹: 3453, 3254, 1672, 1510, 1428.

¹H-NMR (CDCl₃) δ:

-   -   1.20 (3H, t, J=7.4 Hz), 1.22 (3H, t, J=7.4 Hz),     -   2.42 (3H, s), 2.82 (2H, q, J=7.4 Hz),     -   3.06 (2H, q, J=7.4 Hz), 4.18 (2H, s), 6.63 (1H, s),     -   7.33 (1H, m), 7.42 (1H, m), 7.77 (1H, m), 7.91 (1H, m),     -   8.95 (1H, br s).

EIMS m/z (relative intensity): 435 (M⁺), 148 (100).

Elemental analysis: as C₁₉H₂₁N₃OS₄

calculated: C, 52.39; H, 4.86; N, 9.65.

found: C, 52.40; H, 4.86; N, 9.53.

Example 30 Compound No. 825 in Table Production of 6-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 81-83° C.

IR (KBr) cm⁻¹: 3150, 2927, 1647, 1524, 1428.

¹H-NMR (d6-DMSO) δ:

-   -   1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),     -   1.57 (2H, m), 1.69 (2H, m), 1.84 (2H, m), 2.29 (2H, m),     -   2.42 (3H, s), 2.93 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz), 3.36 (2H, t, J=7.3 Hz),     -   6.87 (1H, s), 7.33 (1H, m), 7.43 (1H, m),     -   7.82 (1H, m), 7.92 (1H, m), 8.77 (1H, br s).

EIMS m/z (relative intensity): 491 (M⁺), 168 (100).

Elemental analysis: as C₂₃H₂₉N₃OS₄

calculated: C, 56.18; H, 5.94; N, 8.55; S, 26.08.

found: C, 56.19; H, 5.91; N, 8.43; S, 26.06.

Example 31 Compound No. 828 in Table Production of 9-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 28 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 88-92° C.

IR (KBr) cm⁻¹: 3433, 3241, 2928, 1668, 1510.

¹H-NMR (d6-DMSO) δ:

-   -   1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),     -   1.28-1..54 (8H, m), 1.62 (2H, m),     -   1.80 (2H, quint, J=7.2 Hz), 2.24 (2H, m),     -   2.42 (3H, s), 2.93 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz), 3.35 (2H, t, J=7.2 Hz),     -   6.87 (1H, s), 7.33 (1H, m), 7.43 (1H, m),     -   7.81 (1H, m), 7.92 (1H, m), 8.72 (1H, br s).

Example 32 Compound No. 831 in Table Production of 2-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 26 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 182-183° C.

IR (KBr) cm⁻¹: 3148, 2928, 1674, 1524, 1412.

¹H-NMR (d6-DMSO) δ:

-   -   1.21 (3H, t, J=7.3 Hz), 1.21 (3H, t, J=7.3 Hz),     -   2.41 (3H, s), 2.90 (2H, q, J=7.3 Hz),     -   3.03 (2H, q, J=7.3 Hz), 4.15 (2H, br s),     -   6.87 (1H, s), 7.08-7.12 (2H, m), 7.39-7.44 (2H, m).

EIMS m/z (relative intensity): 418 (M⁺), 357 (100).

Elemental analysis: as C₁₉H₂₂N₄OS₃

calculated: C, 54.52; H, 5.30; N, 13.38.

found: C, 54.44; H, 5.30; N, 13.16.

Example 33 Compound No. 835 in Table Production of 6-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 139-142° C.

IR (KBr) cm⁻¹: 3433, 3143, 2928, 1660, 1510.

¹H-NMR (CDCl₃) δ:

-   -   1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),     -   1.54 (2H, m), 1.68 (2H, m), 1.77 (2H, m), 2.28 (2H, m),     -   2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz), 3.27 (2H, t, J=7.2 Hz),     -   6.87 (1H, s), 7.05-7.11 (2H, m), 7.27-7.52 (2H, m),     -   8.75 (1H, br s), 12.05 (1H, br s).

Example 34 Compound No. 838 in Table Production of 9-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 28 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 76-78° C.

IR (KBr) cm⁻¹: 3104, 2928, 2854, 1658, 1526.

¹H-NMR (d6-DMSO) δ:

-   -   1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),     -   1.28-1.49 (8H, m), 1.61 (2H, m),     -   1.73 (2H, quint, J=7.2 Hz), 2.24 (2H, m),     -   2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz), 3.26 (2H, t, J=7.2 Hz),     -   6.87 (1H, s), 7.05-7.10 (2H, m), 7.24-7.54 (2H, m),     -   8.71 (1H, br s) 12.05 (1H, br s).

Example 35 Compound No. 841 in Table Production of 2-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide

To a 2-propanol (50 ml) -solution of sodium isopropoxide (2.05 g, 25 mmol) was added dropwise 2-propanethiol (1.90, 25 mmol) while being cooled with ice, and the mixtrue was stirred for 30 minutes. While being cooled with ice, a DMF (40 ml) solution of 2,4-dichloro-6-methyl-3-nitropyridine (2.07 g, 10 mmol) was slowly added thereto dropwise. After the mixture was stirred for 2 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off to obtain 2.77 g (yield 97%) of 2,4-bis(isopropylthio)-6-methyl-3-nitropyridine as a yellow needle crystal.

This nitropyridine (1.08 g, 3.77 mmol) was dissolved in a mixed solvent of acetic acid (35 ml) and conc. hydrochloric acid (1.6 ml), and zinc (2.96 g, 45.25 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 1 hour, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through silica gel column chromatography (eluent—hexane:ethyl acetate=30:1→10:1) to obtain 774 mg (yield 80%) of 3-amino-2,4-bis(isopropylthio)-6-methylpyridine as a yellow oil. Triethylamine (336 mg, 3.32 mmol) was added to a THF (10 ml) solution of this aminopyridine (774 mg, 3.02 mmol), and bromoacetyl bromide (732 mg, 3.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (eluent—hexane:ethyl acetate=10:1) to obtain 595 mg (yield 52%) of 2-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide as a colorless powdery crystal. sodium hydrogencarbonate (29 mg, 0.35 mmol) was added to an acetonitrile (5 ml) solution of this amide (132 mg, 0.35 mmol) and 2-mercaptobenzoxazole (53 mg, 0.35 mmol), and the mixture was stirred at room temperature for 28 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:benzen=6:1) to obtain 69 mg (yield 44%) of the desired compound as a colorless powdery crystal.

Melting point: 151-152° C.

IR (KBr) cm⁻¹: 3404, 2967, 1743, 1637, 1360.

¹H-NMR (CDCl₃) δ:

-   -   1.37-1.40 (12H, m), 2.52 (3H, s),     -   3.58 (1H, sept, J=6.8 Hz),     -   4.06 (2H, s), 4.11 (1H, sept, J=6.8 Hz), 6.01 (1H, s),     -   6.81-6.86 (2H, m), 6.92 (1H, dd, J=8.1, 1.3 Hz),     -   7.00-7.07 (2H, m).

Example 36 Compound No. 845 in Table Production of 6-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 35 except that 6-bromohexanoyl chloride was used instead of bromoacetyl bromide to obtain 6-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide. To a DMF (4 ml) solution of this amide (100 mg, 0.23 mmol) and 2-mercaptobenzoxazole (35 mg, 0.23 mmol) were added potassium carbonate (38 mg, 0.28 mmol) and 18-crown-6 (6 mg, 0.02 mmol), and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was allowed to cool, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:1) to obtain 92 mg (yield 79%) of the desired compound as a colorless powdery crystal.

Melting point: 98-100° C.

IR (KBr) cm⁻¹: 3135, 2961, 1648, 1498, 1454, 1133.

¹H-NMR (d6-DMSO) δ:

-   -   1.32 (6H, d, J=6.8 Hz), 1.35 (6H, d, J=6.8 Hz),     -   1.55-1.64 (2H, m), 1.65-1.75 (2H, m),     -   1.82-1.92 (2H, m), 2.23-2.36 (2H, m), 2.46 (3H, s),     -   3.38 (2H, t, J=7.1 Hz), 3.59 (1H, sept, J=6.8 Hz),     -   3.93 (1H, sept, J=6.8 Hz), 6.96 (1H, s),     -   7.29-7.37 (2H, m), 7.57-7.64 (2H, m),     -   8.95 (1H, br s).

Example 37 Compound No. 1237 in Table Production of 6-(oxazolo[4,5-b]pyridin-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide

To a DMF (4 ml) solution of 6-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide (100 mg, 0.27 mmol) and 2-mercaptoxazolo[4,5-b]pyridine (40 mg, 0.27 mmol) were added 18-crown-6 (7 mg, 0.03 mmol) and potassium carbonate (40 mg, 0.29 mmol), and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:acetone=2:1) to obtain 85 mg (yield 72%) of the desired compound as a colorless powdery crystal.

Melting point: 132-133° C.

IR (KBr) cm⁻¹: 3435, 3243, 2923, 1655, 1493, 1404.

¹H-NMR (d6-DMSO) δ:

-   -   1.53-1.63(2H,m), 1.65-1.76(2H,m), 1.83-1.93(2H,m),     -   2.27-2.35(2H,m), 2.40(3H,s),2.42(3H,s),2.45(3H,s),     -   3.40(2H,t,J=7.3Hz), 6.86(1H,S),     -   7.30(1H,dd,J=8.1,4.9Hz), 7.97(1H,dd,J=8.1,1.3HZ),     -   8.42(1H,dd,J=4.9,1.3HZ), 8.83(1H,br s).

EIMS m/z (relative intensity): 447 (M⁺−1), 400(100).

Elemental analysis: as C₂₀H₂₄N₄O₂S₃

calculated: C, 53.55; H, 5.39; N, 12.59; S, 21.44.

found: C, 53.72; H, 5.39; N, 12.41; S, 21.51.

Example 38 Compound No. 1238 in Table Production of 6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manners as in Example 37 except that 7-methoxycarbonyl-2-mercaptobenzoxazole was used instead of 2-mercaptoxazolo[4,5-b]pyridine to obtain the desired compound as a colorless powdery crystal.

Melting point: 141-142° C.

IR (KBr) cm⁻¹: 3425, 3236, 2923, 1726, 1667, 1509.

¹H-NMR (d6-DMSO) δ:

-   -   1.54-1.63(2H,m), 1.67-1.76(2H,m), 1.84-1.93(2H,m),     -   2.28-2.35(2H,m), 2.40(3H,s), 2.42(3H,s), 2.45(3H,s),     -   3.39(2H,t,J=7.1Hz), 3.95(3H,s), 6.86(1H,s),     -   7.44(1H,t,J=7.8Hz), 7.81(1H,dd,J=7.8,1.2Hz),     -   7.85(1H,dd,J=7.8,1.2Hz), 8.82(1H,br s).

EIMS m/z (relative intensity): 504 (M⁺−1), 167(100).

Elemental analysis: as C₂₃H₂₇N₃O₄S₃

calculated: C, 54.63; H, 5.38; N, 8.31; S, 19.02.

found: C, 54.70; H, 5.37; N, 8.27; S, 19.15.

Example 39 Compound No. 1240 in Table Production of 9-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide

To a DMF (4 ml) solution of 9-bromo-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]nonanamide (90 mg, 0.22 mmol) and 7-methoxycarbonyl-2-mercaptobenzoxazole (45 mg, 0.22 mmol) were added 18-crown-6 (6 mg, 0.02 mmol) and potassium carbonate (36 mg, 0.26 mmol), and the mixture was stirred at 80° C. for 4 hours. The rdaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was recrystallized from a mixture of ethyl acetate and hexane to obtain 84 mg (yield 72%) of the desired compound as a colorless powdery crystal.

Melting point: 126-128° C.

IR (KBr) cm⁻¹: 3231, 2924, 1720, 1657, 1508, 1297

¹H-NMR (d6-DMSO) δ:

-   -   1.27-1.47(8H,m), 1.54-1.62(2H,m), 1.74-1.85(2H,m),     -   2.24(2H,t,J=7.3 Hz), 2.37(3H,s),2.38(3H,s),2.43(3H,s),     -   3.31-3.41(2H,m), 3.91(3H,s), 6.86(1H,s),     -   7.45(1H,t,J=7.8 Hz), 7.81(1H,dd,J=7.8,1.0 Hz),     -   7.91(1H,dd,J=7.8,1.0 Hz), 9.26(1H,s).

EIMS m/z (relative intensity): 546(M⁺−1), 500(100).

Elemental analysis: as C₂₆H₃₃N₃O₄S₃

calculated: C, 57.01; H, 6.07; N, 7.67; S, 17.56.

found: C, 57.10; H, 5.95; N, 7.67; S, 17.60.

Examples 40 Compound No. 151 in Table Production of 2-(benzoxazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)acetamide

The reaction and the treatment were conducted in the same manner as in Example 16 except that 3-amino-4-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless needle crystal.

Melting point: 146-148° C.

IR (KBr) cm⁻¹: 3437, 3245, 1671, 1659, 1507, 1454.

¹H-NMR (CDCl₃) δ:

-   -   2.17 (3H, s), 2.42 (3H, s), 4.11 (2H, s),     -   6.87 (1H, d, J=4.9 Hz),     -   7.28-7.34 (2H, m), 7.50 (1H, m), 7.61 (1H, m),     -   8.23 (1H, d, J=4.9 Hz), 8.88 (1H, br s).

EIMS m/z (relative intensity): 345 (M⁺, 100).

Elemental analysis: as C₁₆H₁₅N₃O₂S₂

calculated: C, 55.63; H, 4.38; N, 12.16; S, 18.56.

found: C, 55.66; H, 4.46; N, 12.02; S, 18.55.

Example 41 Compound No. 155 in Table Production of 6-(benzoxazol-2-ylthio)-N-(4-methyl-2-methylthio-3-pyridyl)hexanamide

The reaction and the treatment were conducted in the same manner as in Example 18 except that 3-amino-4-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless needle crystal.

Melting point: 122-124° C.

IR (KBr) cm⁻¹: 3437, 3245, 1660, 1521, 1507, 1133.

¹H-NMR (d₆-DMSO) δ:

-   -   1.49-1.56 (2H, m), 1.68 (2H, quint, J=7.4 Hz),     -   1.84 (2H, quint, J=7.4 Hz), 2.09 (3H, s),     -   2.33 (2H, t, J=7.4 Hz), 2.40 (3H, s),     -   3.36 (2H, t, J=7.4 Hz),     -   7.02 (1H, d, J=4.9 Hz), 7.29-7.36 (2H, m),     -   7.61-7.66 (2H, m),8.24 (1H, d, J=4.9 Hz),     -   9.40 (1H, br s).

EIMS m/z (relative intensity): 401 (M⁺, 100).

Elemental analysis: as C₂₀H₂₃N₃O₂S₂

calculated: C, 59.82; H, 5.77; N, 10.46; S, 15.97.

found: C, 59.93; H, 5.89; N, 10.34; S, 15.99.

Example 42 Compound No. 365 in Table Production of 6-(benzoxasole-2-ylthio)-N-(6-methoxy-2-methylthio-3-pyridyl)hexanamide

A methanol (100 ml) solution of 2-chloro-6-methoxy-3-nitropyridine (2.0 g, 10.4 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (805 mg, 10.9 mmol) while being cooled with ice, and the temperature thereof was raised to the room temperature and the mixed solution was stirred for 17 hours and the precipitated crystal was filtered to obtain 1.26 g (yield 59%) of 6-methoxy-2-methylthio-3-nitropyridine as a yellow powdery crystal,

This nitropyridine (400 mg, 2.0 mmol) was dissolved in a mixed solvent of acetic acid (20 ml) and conc. hydrochloric acid (0.5 ml), and zinc (1.57 g, 24.0 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 40 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=6:1→4:1) to obtain 264 mg (yield 78%) of 3-amino-6-methoxy-2-methylthiopyridine as a pale brown powdery crystal.

And then the reaction and the treatment were conducted in the same manner as. in Example 18 except that 3-amino-6-methoxy-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methlthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.

Melting point: 102-104° C.

IR (KBr) cm⁻¹: 3430, 3224, 2940, 1652, 1591.

¹H-NMR (CDCl₃) δ:

-   -   1.61 (2H, quint, J=7.4 Hz),     -   1.82 (2H, quint, J=7.4 Hz),     -   1.92 (2H, quint, J=7.4 Hz), 2.42 (2H, t, J=7.4 Hz),     -   2.59 (3H, s), 3,134 (2H, t, J=7.4 Hz), 3.94 (3H, s),     -   6.47 (1H, d, J=8.5 Hz), 6.91 (1H, br s),     -   7.23 (1H, td, J=7.7, 1.5 Hz),     -   7.27 (1H, td, J=7.7, 1.5 Hz),     -   7.43 (1H, dd, J=7.7, 1.5 Hz),     -   7.58 (1H, dd, J=7.7, 1.5 Hz), 7.93 (1H, d, J=8.5 Hz).

EIMS m/z (relative intensity): 417 (M⁺), 171 (100).

Example 43 Compound No. 451 in Table Production of 2-(benzoxazol-2-ylthio)-N-(6-methylthio-3-pyridyl)acetamide

The reaction and the treatment were conducted in the same manner as in Example 16 except that 3-amino-6-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless needle crystal.

Melting point: 180-181° C.

IR (KBr) cm⁻¹: 3437, 3254, 1661, 1534, 1509, 1135.

¹H-NMR (CDCl₂) δ:

-   -   2.46 (3H, s), 2.50 (3H, s), 4.10 (2H, s),     -   6.87 (2H, d, J=8.1 Hz),     -   7.26-7.34 (2H, m), 7.48 (1H, m), 7.62 (1H, m),     -   8.12 (2H, d, J=8.1 Hz), 9.27 (1H, br s).

EIMS m/z (relative intensity): 345 (M⁺), 298 (100).

Elemental analysis: as C₁₆H₁₅N₃O₂S₂

calculated: C, 55.63; H, 4.38; N, 12.16; S, 18.56.

found: C, 55.62; H, 4.40; N, 12.10; S, 18.50.

Example 44 Compound No. 461 in Table Production of 2-(benzothiazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)acetamide

The reaction and the treatment were conducted in the same manner as in Example 43 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting Point: 175-176° C.

IR (KBr) cm⁻¹: 3437, 3248, 1656, 1532, 1430.

¹H-NMR (CDCl₃) δ:

-   -   2.45 (3H, s), 2.47 (3H, s), 4.18 (2H, s),     -   6.87 (1H, d, J=8.1 Hz),     -   7.34 (1H, m), 7.44 (1H, m), 7.77 (1H, m), 8.01 (1H, m),     -   8.07 (1H, d, J=8.1 Hz), 9.31 (1H, br s).

EIMS m/z (relative intensity): 361 (M⁺), 210 (100).

Elemental analysis: as C₁₆H₁₅N₃OS₃

calculated: C, 53.16; H, 4.18; N, 11.62; S, 26.61.

found: C, 53.23; H, 4.25; N, 11.55; S, 26.67.

Example 45 Compound No. 471 in Table Production of 2-(benzimidazol-2-ylthio)-N-(6-methyl-2-methylthio-3-pyridyl)acetamide

The reaction and the treatment were conducted in the same manner as in Example 43 except that 2-2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 192-193° C. (d.)

IR (KBr) cm⁻¹: 3420, 3249, 1667, 1550, 1438, 744.

¹H-NMR (CDCl₃) δ:

-   -   2.45 (3H, s), 2.50 (3H, s), 4.08 (2H, s),     -   6.84 (1H, d, J=8.1 Hz),     -   7.19-7.25 (2H, m), 7.35 (1H, m), 7-.73 (1H, m),     -   8.00 (1H, d, J=8.1 Hz), 9.95 (1H, br s),     -   10.00 (1H, br s).

EIMS m/z (relative intensity): 344 (M⁺), 118 (100).

Elemental analysis: as C₁₆H₁₆N₄OS₂

calculated: C, 55.79; H, 4.68; N, 16.27; S, 18.62.

found: C, 55.80; H, 4.68; N, 16.16; S, 18.65.

Example 46 Compound No. 784 in Table Production of 5-(benzoxazol-2-ylthio)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)pentanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 5-bromopentqnoic acid chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless needles crystal.

Melting point: 147-150° C.

IR (KBr) cm⁻¹: 3230, 1664, 1501, 1455, 1136.

¹H-NMR (d₆-DMSO) δ:

-   -   1.72-1.96 (4H, m), 2.3-6 (3H, s),     -   2.26-2.42 (2H, m),     -   2.39 (3H, s), 2.43 (3H, s), 3.36 (2H, t, J=7.2 Hz),     -   6.83 (1H, s),     -   7.23-7.33 (2H, m), 7.52-7.59 (2H, m),     -   8.74 (1H, br s).

EIMS m/z (relative intensity): 433 (M⁺), 201 (100).

Example 47 Compound No. 786 in Table Production of 7-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 7-bromoheptanonyl chloride was used instead of 4-bromobutanoyl chloride to obtain the desired compound as a colorless powdery crystal.

Melting point: 137-139° C.

IR (KBr) cm⁻¹: 3437, 3242, 2922, 2857, 1660, 1500, 1455, 1132.

¹H-NMR (d₆-DMSO) δ:

-   -   1.41-1.54 (4H, m), 1.60-1.70 (2H, m),     -   1.81 (2H, quint, J=7.1 Hz), 2.26-2.32 (2H, m),     -   2.38 (3H, s), 2.40 (3H, s), 2.43 (3H, s),     -   3.33 (2H, t, J=7.1 Hz),     -   6.81 (1H, s), 7.27 (1H, td, J=7.6 , 1.7 Hz),     -   7.30 (1H, td, J=7.6 , 1.7 Hz), 7.54-7.60 (2H, m),     -   8.79 (1H, br s).

EIMS m/z (relative intensity): 461 (M⁺), 200 (100).

Example 48 Compound No. 787 in Table Production of 8-(benzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 17 except that 8-bromooctanoyl chloride was used instead of 4-bromobutanonyl chloride to obtain the desired compound as a colorless prism crystal.

Melting point: 119-122° C.

IR (KBr) cm⁻¹: 3435, 3248, 2923, 2856, 1660, 1501, 1454, 1131.

¹H-NMR (d₆-DMSO) δ:

-   -   1.33-1.52 (6H, m), 1.58-1.69 (2H, m),     -   1.81 (2H, quint, J=7.1 Hz), 2.26-2.32 (2H, m),     -   2.38 (3H, s),     -   2.41 (3H, s), 2,.44 (3H, s), 3.33 (2H, t, J=7.1 Hz),     -   6.84 (1H, s), 7.27 (1H, td, J=7.6 , 1.7 Hz),     -   7.30 (1H, td, J=7.6 , 1.7 Hz), 7.54-7.60 (2H, m),     -   8.77 (1H, br s).

EIMS m/z (relative intensity): 475 (M⁺), 200 (100).

Example 49 Compound No. 791 in Table Production of 2-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide

An acetonitrile solution (6 ml) of 2-bromo-N-[2,4-bis(methylthio)-3-pyridyl]acetamide (64 mg, 0.2 mmol) was added to an acetonitrile solution (1 ml) of sodium hydrogencarbonate (17 mg, 0.2 mmol) and 2-mercaptobenzothiazole (34 mg, 0.2 mmol), and the mixed solution was stirred for 48 hours at the room temperature. And the solution of reaction mixture was concentrated under reduced pressure, and the residue was extraxted with ethyl acetate after dilluting with water. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through preparative thin layer chromatography (eluent—chloroform:methanol=20:1) to obtain 46 mg (yield 33%) as a colorless needle crystal.

Melting point: 178-179° C.

IR (KBr) cm⁻¹: 3437, 3246, 1665, 1564, 1497, 1430.

¹H-NMR (CDCl₃) δ:

-   -   2.33 (3H, s), 2.44 (3H, s), 2.46 (3H, s), 4.17 (2H, s),     -   6.61 (1H, s), 7.33 (1H, m), 7.43 (1H, m), 7.78 (1H, m),     -   7.90 (1H, m), 9.,11 (1H, br s).

EIMS m/z (relative intensity): 407 (M⁺), 209 (100).

Elemental analysis: as C₁₇H₁₇N₃OS₄

calculated: C, 50.10; H, 4.20; N, 10.31; S, 31.46.

found: C, 50.18; H, 4.29; N, 10.23; S, 31.49.

Example 50 Compound No. 794 in Table Production of 5-(benzothiazol-2-ylthio)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)pentanamide

The reaction and the treatment were conducted in the same manner as in Example 46 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 121-123° C.

IR (KBr) cm⁻¹: 3437, 3240, 2923, 1664, 1515, 1456, 1428, 995.

¹H-NMR (d₆-DMSO) δ:

-   -   1.78-1.87 (2H, m), 1.88-1.96 (2H, m),     -   2.30-2.40 (2H, m),     -   2.38 (3H, s), 2.41 (3H, s), 2.45 (3H, s),     -   3.41 (2H, t, J=7.1 Hz),     -   6.85 (1H, s), 7.34 (1H, t, J=7.6 Hz),     -   7.45 (1H, t, J=7.6 Hz),     -   7.84 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=7.6 Hz),     -   8.87 (1H, br s).

EIMS m/z (relative intensity): 449 (M⁺), 201 (100).

Example 51 Compound No. 796 in Table Production of 7-(benzothiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)heptamamide

The reaction and the treatment were conducted in the same manner as in Example 47 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 129-130° C.

IR (KBr) cm⁻¹: 3436, 3245, 2922, 1661, 1506, 1428.

¹H-NMR (d₆-DMSO) δ:

-   -   1.44-1.54 (4H, m), 1.62-1.71 (2H, m),     -   1.83 (2H, quint, J=7.2 Hz), 2.13-2.33 (2H, m),     -   2.39 (3H, s), 2.42 (3H, s), 2.45 (3H, s),     -   3.37 (2H, t. J=7.2 Hz), 6.86 (1H, s),     -   7.34 (1H, td, J=7.8, 1.2 Hz),     -   7.45 (1H, td, J=7.8, 1.2 Hz),     -   7.84 (1H, dd, J=7.8, 1.2 Hz),     -   7.94 (1H, dd, J=7.8, 1.2 Hz),     -   8.81 (1H, br s).

EIMS m/z (relative intensity): 477 (M⁺), 200 (100).

Elemental analysis: as C₂₂H₂₇N₃OS₄

calculated: C, 55.31; H, 5.70; N, 8.80.

found: C, 55.41; H, 5.71; N, 8.64.

Example 52 Compound No. 797 in Table Production of 8-(benzthiazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)octanamide

The reaction and the treatment were conducted in the same manner as in Example 48 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 104-108° C.

IR (KBr) cm⁻¹: 3242, 2925, 1665, 1508, 1459, 1428.

¹H-NMR (d₆-DMSO) δ:

-   -   1.30-1.51 (6H, m), 1.55-1.69 (2H, m),     -   1.81 (2H, quint, J=7.1 Hz), 2.23-2.29 (2H, m),     -   2.38 (3H, s), 2.41. (3H, s), 2.44 (3H, s),     -   3.35 (2H, t, J=7.2 Hz)     -   6.83 (1H, s), 7.32 (1H, m), 7.43 (1H, m), 7.81 (1H, m),     -   7.91 (1H, m), 8.76 (1H, br s).

EIMS m/z (relative intensity): 491 (M⁺), 200 (100).

Example 53 Compound No. 801 in Table Production of 2-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl)pentanamide

The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenothiazole to obtain the desired compound as a colorless needle crystal.

Melting point: 235-237° C. (d.)

IR (KBr) cm⁻¹: 3429, 3243, 2978, 2923, 1661, 1505, 1439.

¹H-NMR (CDCl₃) δ:

-   -   2.35 (3H, s), 2.46 (3H, s), 2.47 (3H, s), 4.03 (2H, s),     -   6.63 (1H, s), 7.21 (1H, t, J=6.1 Hz),     -   7.22 (1H, t, J=6.1 Hz),     -   7.43-7.60 (2H, m), 9.43 (1H, br s).

EIMS m/z (relative intensity): 390 (M⁺), 344 (100).

Example 54 Compound No. 804 in Table Production of 5-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 46 except that 2-mercaptobenzimdazole was used instead of 2-mercaptobenoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 176-177° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.74-1.84 (4H, m), 2.26-2.35 (2H. m). 2.36 (3H, s),     -   2.39 (3H, s), 2.43 (3H, s), 3.26-3.36 (2H, m),     -   6.84 (1H, s), 7.04-7.13 (2H, m), 7.34-7.45 (2H, m),     -   8.84 (1H, br s), 12.06 (1H, br s).

EIMS m/z (relative intensity): 432 (M⁺), 200 (100).

Example 55 Compound No. 806 in Table Production of 7-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 47 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.

Melting point: 189-192° C.

IR (KBr) cm⁻¹: 3139, 2925, 2854, 1668, 1561, 1523, 1435, 1401.

¹H-NMR (d₆-DMSO) δ:

-   -   1.39-1.52 (4H, m), 1.56-1.70 (2H, m),     -   1.75 (2H, quint, J=7.1 Hz), 2.28-2.34 (2H, m),     -   2.38 (3H, s), 2.40 (3H, s), 2.43 (3H, s),     -   3.27 (2H, t, J=7.1 Hz), 6.84 (1H, s),     -   7.07 (1H, t, J=7.1 Hz), 7.08(1H, t, J=7.1 Hz),     -   7.32 (1H, d, J=7.1 Hz), 7.46 (1H, d, J=7.1 Hz),     -   8.79 (1H, br s).

EIMS m/z (relative intensity): 460 (M⁺), 150 (100).

Example 56 Compound No. 807 in Table Production of 8-(benzimidazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 48 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 186-187° C.

IR (KBr) cm⁻¹: 3430, 3222, 2925, 1661, 1564, 1522, 1437, 808.

¹H-NMR (d₆-DMSO) δ:

-   -   1.35-1.43 (4H, m), 1.47 (2H, quint, J=7.2 Hz),     -   1.60-1.68 (2H, m), 1.76 (2H, quint, J=7.2 Hz),     -   2.23-2.32 (2H, m), 2.40 (3H, s), 2.42 (3H, s),     -   2.45 (3H,s), 3.28 (2H, t, J=7.2 Hz), 6.89 (1H, s),     -   7.09 (1H, t, J=5.9 Hz),     -   7.09 (1H, t, J=5.9 Hz), 7.40 (1H, d, J=5.9 Hz),     -   7.41 (1H, d, J=5.9 Hz), 8.80 (1H, br s).     -   12.09 (1H, br s).

EIMS m/z (relative intensity): 474 (M⁺), 150 (100).

Example 57 Compound No. 813 in Table Production of 4-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 4-bromobutanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless crystal.

Melting point: 12.3-125° C.

IR (KBr) cm⁻¹: 3436, 3239, 2974, 2929, 1656, 1502, 1454, 1130.

¹H-NMR (d₆-DMSO) δ:

-   -   1.23-1.28 (6H, m),2.12-2.19 (2H, m), 2.43 (3H, s),     -   2.48-2.50 (2H,m), 2.93 (2H, q, J=7.1 Hz),     -   3.06 (2H, q, J=7.1 Hz), 3.41-3.48 (2H, m),     -   6.89 (3H, s), 7.29-7.34 (2H. m), 7.56-7.62 (2H, m),     -   8.96 (1H, br s).

EIMS m/z (relative intensity): 447 (M⁺), 227 (100).

Example 58 Compound No. 814 in Table Production of 5-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 5-bromopentanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.

Melting point: 122-123° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),     -   1.76-1.87 (2H, m), 1.87-1.97 (2H, m),     -   2.29-2.40 (2H, m), 2.43 (3H, s),     -   2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz),     -   3.38 (2H, t, J=7.2 Hz), 6.88 (1H, s),     -   7.26-7.35 (2H, m), 7.55-7.60 (2H, m),     -   8.82 (1H, br s).

EIMS m/z (relative intensity): 461 (M⁺), 227 (100).

Example 59 Compound No. 816 in Table Production of 7-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 7-bromoheptanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.

Melting point: 103-105° C.

IR (KBr) cm⁻¹: 3247, 1663, 1501, 1455.

¹H-NMR (d₆-DMSO) δ:

-   -   1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz),     -   1.38-1.54 (4H, m), 1.57-1.72 (2H, m),     -   1.73-1.89 (2H, m), 2.19-2.32 (2H, m), 2.41 (3H, s),     -   2.92 (2H, q, J=7.3 Hz), 3.05 (2H, q, J=7.3 Hz),     -   3.33 (2H, t, J=7.1 Hz), 6.86 (1H, s),     -   7.24-7.32 (2H, m), 7.52-7.60 (2H, m),     -   8.65 (1H, br s).

EIMS m/z (relative intensity): 489 (M⁺), 228 (100).

Example 60 Compound No. 817 in Table Production of 8-(benzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 27 except that 8-bromooctanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.

Melting point: 82-84° C.

IR (KBr) cm⁻¹: 3449, 3245, 2932, 1669, 1500, 1455, 1132.

¹H-NMR (d₆-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz),     -   1.37-1.42 (4H, m), 1.48 (2H, quint. J=7.2 Hz),     -   1.60-1.67 (2H, m), 1.82 (2H, quint. J=7.2 Hz),     -   2.24-2.30 (2H, m), 2.43 (3H, s),     -   2.94 (2H, q, J=7.3 Hz),     -   3.07 (2H, q, J=7.3 Hz), 3.34 (2H, t, J=7.2 Hz),     -   6.88 (1H, s), 7.27-7.33 (2H, m), 7.56-7.61 (2H, m),     -   8.73 (1H, br s).

EIMS m/z (relative intensity): 503 (M⁺), 229 (100).

Example 61 Compound No. 823 in Table Production of 4-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 57 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 119-120° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.25 (3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.4 Hz),     -   2.07-2.23 (2H, m), 2.43 (3H, s), 2.45-2.55 (2H, m,),     -   2.93 (2H, q, J=7.4 Hz), 3.06 (2H, q, J=7.4 Hz),     -   3.41-3.54 (2H, m), 6.89 (1H, s), 7.35 (1H, t, J=8.1 Hz),     -   7.45 (1H, t, J=8.1 Hz), 7.83 (1H, d, J=8.1 Hz).     -   7.94 (1H, d, J=8.1 Hz), 8.95 (1H, br s).

EIMS m/z (relative intensity): 463 (M⁺), 229 (100).

Example 62 Compound No. 824 in Table Production of 5-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 58 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 102-104° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.25 (3H, t, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz),     -   1.77-1.88 (2H, m), 1.88-2.00 (2H, m),     -   2.29-2.41 (2H, m), 2.43 (3H, s),     -   2.93 (2H, q, J=7.3 Hz),     -   3.06 (2H, q, J=7.3 Hz),     -   3.41 (2H, t, J=7.0 Hz), 6.89 (1H, s),     -   7.35 (1H, ddd, J=8.2 , 7.2 , 1.2 Hz),     -   7.45 (1H, ddd, J=8.2 , 7.2 , 1.2 Hz),     -   7.84 (1H, dd, J=8.2 , 1.2 Hz),     -   7.94 (1H, dd, J=8.2 , 1.2 Hz), 8.84 (1H, br s).

EIMS m/z (relative intensity): 477 (M⁺), 229 (100).

Example 63 Compound No. 826 in Table Production of 7-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 59 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting Point: 114-116° C.

IR (KBr) cm⁻¹: 3245, 1665, 1536, 1509, 1426.

¹H-NMR (d₆-DMSO) δ:

-   -   1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz),     -   1.39-1.56 (4H, m), 1.58-1.71 (2H, m),     -   1.75-1.88 (2H, m), 2.19-2.31 (2H, m), 2.42 (3H, s),     -   2.92 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz), 3.35 (2H, t, J=7.2 Hz),     -   6.86 (1H, s), 7.32 (1H, td, J=7.6 , 1.2 Hz),     -   7.42 (1H, td, J=7.6 , 1.2 Hz),     -   7.81 (1H, dd, J=7.6 , 1.2 Hz),     -   7.91 (1H, dd, J=7.6 , 1.2 Hz),     -   8.67 (1H, br s).

EIMS m/z (relative intensity): 505 (M⁺), 227 (100).

Example 64 Compound No. 827 in Table Production of 8-(benzothiazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 60 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 94-96° C.

IR (KBr) cm⁻¹: 3433, 3243, 2929, 1669, 1511, 1428.

¹H-NMR (d₆-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz),     -   1.37-1.43 (4H, m), 1.45-1.52 (2H, m),     -   1.57-1.68 (2H, m), 1.82 (2H, quint, J=7.2 Hz),     -   2.20-2.32 (2H, m), 2.43 (3H, s),     -   2.94 (2H, q, J=7.3 Hz), 3.07 (2H, q, J=7.3 Hz),     -   3.37 (2H, t, J=7.2 Hz), 6.88 (1H, s),     -   7.34 (1H, td, J=7.6 , 1.1 Hz),     -   7.44 (1H, td, J=7.6 , 1.1 Hz),     -   7.83 (1H, dd, J=7.6 , 1.1 Hz),     -   7.93 (1H, dd, J=7.6 , 1.1 Hz),     -   8.73 (1H, br s).

EIMS m/z (relative intensity): 519 (M⁺), 227 (100).

Example 65 Compound No. 833 in Table Production of 4-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 57 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow powdery crystal.

Melting point: 160-161° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.25 (3H, t, J 7.3 Hz), 1.26 (3H, t, J 7.3 Hz),     -   2.27-2.37 (2H, m), 2.44 (3H, s),     -   2.48-2.50 (2H, m), 2.93 (2H, q, J=7.3 Hz),     -   3.06 (2H, q, J=7.3 Hz), 3.34-3.46 (2H, m),     -   6.89 (1H, s), 7.05-7.14 (2H, m), 7.33 (1H, m),     -   7.46 (1H, m), 8.95 (1H, br s).

EIMS m/z (relative intensity): 446 (M⁺), 195 (100).

Example 66 Compound No. 834 in Table Production of 5-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 58 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 163-165° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.23 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz),     -   1.74-1.88 (4H, m), 2.27-2.38 (2H, m),     -   2.41 (3H, s), 2.90 (2H, q, J=7.3 Hz),     -   3.03 (2H, q, J=7.3 Hz), 3.26-3.34 (2H, m),     -   6.86 (1H, s), 7.04-7.11 (2H, m),     -   7.32 (1H, m), 7.46 (1H, m), 8.79 (1H, br s).

EIMS m/z (relative intensity): 460 (M⁺), 195 (100).

Example 67 Compound No. 836 in Table Production of 7-(benzimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 59 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 151-156° C.

IR (KBr) cm⁻¹: 3136, 3106, 1656, 1518, 1438. 1401, 1337, 1268.

¹H-NMR (d₆-DMSO) δ:

-   -   1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz),     -   1.36-1.54 (4H, m), 1.55-1.82 (4H, m),     -   2.15-2.32 (2H, m),     -   2.41 (3H, s), 2.92 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz),     -   3.26 (2H, t, J=7.3 Hz), 6.86 (1H, s),     -   7.03-7.11 (2H, m), 7.34-7.44 (2H, m),     -   8.67 (1H, br s).

EIMS m/z (relative intensity): 488 (M⁺), 151 (100).

Example 68 Compound No. 837 in Table Production of 8-(benzoimidazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 60 except that 2-mercaptobenzoimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 166-168° C.

IR (KBr) cm⁻¹: 3427, 3147, 2928, 1660, 1560, 1526, 1437.

¹H-NMR (d₆-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz),     -   1.36-1.41 (4H, m), 1.47 (2H, quint, J=7.2 Hz),     -   1.60-1.67 (2H, m), 1.75 (2H, quint, J=7.2 Hz),     -   2.22-2.32 (2H, m), 2.43 (3H, s),     -   2.94 (2H, q, J=7.3 Hz),     -   3.07 (2H, q, J=7.3 Hz), 3.28 (2H, t, J=7.2 Hz),     -   6.88 (1H, s), 7.08 (1H, t, J=5.9 Hz),     -   7.09 (1H, t, J=5.9 Hz),     -   7.40 (1H, d, J=5.9 Hz), 7.41 (1H, d. J=5.9 Hz),     -   8.73 (1H, br s).

EIMS m/z (relative intensity): 502 (M⁺), 151 (100).

Example 69 Compound No. 843 in Table Production of 4-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 4-bromobutanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.

Melting point: 128-129° C.

IR (KBr) cm⁻¹: 3448, 3235, 2962, 1683, 1657, 1555, 1515, 1500, 1456, 1131.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J=6.6 Hz), 1.30 (6H, d, J=6.8 Hz),     -   2.10-2.17 (2H, m), 2.42 (3H, s),     -   2.47-2.50 (2H, m), 3.39-3.47 (2H, m),     -   3.55 (1H, sept, J=6.6 Hz),     -   3.89 (1H, sept, J=6.8 Hz),     -   6.92 (1H, s), 7.28 (1H, td, J=7.3 , 1.7 Hz),     -   7.30 (1H, td, J=7.3 , 1.7 Hz),     -   7.56 (1H, dd, J=7.3 , 1.7 Hz),     -   7.58 (1H, dd, J=7.3 , 1.7 Hz), 8.90 (1H, br s).

EIMS m/z (relative intensity): 475 (M⁺), 207 (100).

Example 70 Compound No. 844 in Table Production of 5-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 5-bromopentanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless prism crystal.

Melting point: 129-130° C.

IR (KBr) cm⁻¹: 3448, 3215, 3167, 2965, 1654, 1555, 1525, 1500, 1454, 1128.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz),     -   1.75-1.85 (2H, m), 1.86-1.96 (2H, m),     -   2.26-2.40 (2H, m),     -   2.42 (3H, s), 3.37 (2H, t, J=7.1 Hz),     -   3.54 (1H, sept, J=6.8 Hz),     -   3.88 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.27 (1H, td, J=7.6 , 1.7 Hz),     -   7.30 (1H, td, J=7.6 , 1.7 Hz),     -   7.55 (1H, dd, J=7.6 , 1.7 Hz),     -   7.58 (1H, dd, J=7.6 , 1.7 Hz), 8.75 (1H, br s).

EIMS m/z (relative intensity): 489 (M⁺), 221 (100).

Example 71 Compound No. 846 in Table Production of 7-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 7-bromoheptanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless needle crystal.

Melting point: 76-78° C.

IR (KBr) cm⁻¹: 3436, 3265, 2929, 1663, 1503, 1455.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.8 Hz), 1.32 (6H, d, J=6.8 Hz),     -   1.43-1.54 (4H, m), 1.65 (2H, quint, J=7.2 Hz),     -   1.83 (2H, quint, J=7.2 Hz), 2.20-2.33 (2H, m),     -   2.43 (3H, s), 3.35 (2H, t, J=7.2 Hz),     -   3.56 (1H, sept, J=6.8 Hz),     -   3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s),     -   7.27-7.34 (2H, m),     -   7.56-7.61 (2H, m), 8.72 (1H, br s).

EIMS m/z (relative intensity): 517 (M⁺), 249 (100).

Example 72 Compound No. 847 in Table Production of 8-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 8-bromooctanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a colorless oil.

IR (KBr) cm⁻¹: 3241, 166.4, 1559, 1526, 1501, 1454.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz),     -   1.34-1.54 (6H, m), 1.55-1.69 (2H, m),     -   1.73-1.89 (2H, m),     -   2.15-2.28 (2H, m), 2.42 (3H, s),     -   3.27 (2H, t, J=7.3 Hz),     -   3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.90 (1H, s), 7.24-7.32 (2H, m), 7.51-7.60 (2H, m),     -   8.59 (1H, br s).

EIMS m/z (relative intensity): 531 (M⁺), 263 (100).

Example 73 Compound No. 848 in Table Production of 9-(benzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 9-bromononanoyl chloride was used instead of 6-bromohexanoyl chloride to obtain the desired compound as a pale yellow oil.

IR (Cap) cm⁻¹: 3243, 2962, 2927, 1668, 1558, 1505, 1455, 1130.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz) 1.31 (6H, d, J=6.8 Hz)     -   1.28-1.50 (8H, m), 1.55-1.65 (2H, m),     -   1.80 (2H, quint, J=7.3 Hz), 2.17-2.27 (2H, m),     -   2.42 (3H, s), 3.32 (2H, t, J=7.3 Hz),     -   3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.27 (1H, td, J=7.3 , 1.7 Hz),     -   7.30 (1H, td, J=7.3 , 1.7 Hz), 7.54-7.60 (2H, m),     -   8.65 (1H, br s).

EIMS m/z (relative intensity): 545 (M⁺), 277 (100).

Example 74 Compound No. 851 in Table Production of 2-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-bromo-N-[2,4-bis(isopropylthio)-6-methy-3-pyridyl]acetamide was used instead of 2-bromo-N-2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide to obtain the desired compound as a colorless needle crystal.

Melting point: 117-118° C.

IR (KBr) cm⁻¹: 3431, 3179, 2967, 1660, 1559, 1526, 1428.

¹H-NMR (CDCl₃) δ:

-   -   1.19 (6H, d, J=6.7 Hz), 1.21 (6H, d, J=6.7 Hz),     -   2.41 (3H, s), 3.39 (1H, sept, J=6.7 Hz),     -   3.92 (1H, sept, J=6.7 Hz),     -   4.18 (2H, s), 6.68 (1H, s),     -   7.32 (1H, td, J=7.7, 1.2 Hz),     -   7.41 (1H, td, J=7.7, 1.2 Hz),     -   7.77 (1H, d, J=7.7 Hz),     -   7.91 (1H, d, J=7.7 Hz), 8.80 (1H, br s).

EIMS m/z (relative intensity): 463 (M⁺), 180 (100).

Elemental Analysis: as C₂₁H₁₅N₃OS₄

Calculated: C, 54.39; H, 5.43; N, 9.06; S, 27.66.

Found:C, 54.28; H, 5.45; N, 8.93; S, 27.73.

Example 75 Compound No. 853 in Table Production of 4-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 69 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 116-117° C.

IR (KBr) cm⁻¹: 3450, 3257, 2962, 1667, 1557, 1510, 1457, 1429, 987.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz),     -   2.08-2.17 (2H, m), 2.42 (3H, s),     -   2.43-2.47 (2H, m), 3.45 (2H, t, J=7.1 Hz),     -   3.55 (1H, sept, J=6.8 Hz),     -   3.89 (1H, sept, J=6.8 Hz), 6.92 (1H, s),     -   7.33 (1H, t, J=7.8 Hz),     -   7.43 (1H, t, J=7.8 Hz), 7.81 (1H, d, J=7.8 Hz),     -   7.92 (1H, d, J=7.8 Hz), 8.90 (1H, br s).

EIMS m/z (relative intensity): 491 (M⁺), 69 (100).

Example 76 Compound No. 854 in Table Production of 5-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 70 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 107-109° C.

IR (KBr) cm⁻¹: 3441, 3215, 2963, 1656, 1557, 1523, 1460, 1429, 996.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J 6.8 Hz), 1.30 (6H, d, J=6.8 Hz),     -   1.76-1.85 (2H, m), 1.86-1.96 (2H, m),     -   2.26-2.40 (2H, m),     -   2.42 (3H, s), 3.39 (2H, t, J=7.1 Hz),     -   3.54 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.33 (1H, td, J=8.1, 1.2 Hz),     -   7.43 (1H, td, J=8.1, 1.2 Hz),     -   7.82 (1H, dd, J=8.1, 1.2 Hz),     -   7.92 (1H, dd, J=8.1, 1.2 Hz), 8.75 (1H, br s).

EIMS m/z (relative intensity): 505 (M⁺), 221 (100).

Example 77 Compound No. 855 in Table Production of 6-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 84-86° C.

IR (KBr) cm⁻¹: 3436, 3212, 2961, 2925, 1655, 1555, 1522, 1428.

¹H-NMR (d₆-DMSO) δ:

-   -   1.30 (6H, d, J=6.6 Hz), 1.33 (6H, d, J=6.8 Hz),     -   1.54-1.62 (2H, m), 1.65-1.73 (2H, m),     -   1.85 (2H, quint, J=7.0 Hz), 2.22-2.33 (2H, m),     -   2.43 (3H, s),     -   3.38 (2H, t, J=7.0 Hz), 3.57 (1H, sept, J=6.6 Hz),     -   3.91 (1H, sept, J=6.8 Hz), 6.93 (1H, s),     -   7.34 (1H, t, J=7.8 Hz),     -   7.44 (1H, t, J=7.8 Hz), 7.83 (1H, d, J=7.8 Hz),     -   7.93 (1H, d, J=7.8 Hz), 8.73 (1H, br s).

EIMS m/z (relative intensity): 519 (M⁺), 235 (100).

Example 78 Compound No. 856 in Table Production of 7-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 71 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 74-76° C.

IR (KBr) cm⁻¹: 3436, 3200, 3158, 2961, 2928, 1654, 1525, 1427.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.6 Hz), 1.32 (6H, d, J=6.8 Hz),     -   1.43-1.55 (4H, m), 1.65 (2H, quint, J=7.2 Hz),     -   1.83 (2H, quint, J=7.2 Hz), 2.22-2.33 (2H, m),     -   2.43 (3H, s), 3.37 (2H, t, J=7.2 Hz),     -   3.56 (1H, sept, J=6.6 Hz),     -   3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s),     -   7.34 (1H, td, J=7.7, 1.2 Hz),     -   7.44 (1H, td, J=7.7, 1.2 Hz),     -   7.83 (1H, dd, J=7.7, 1.2 Hz),     -   7.94 (1H, dd, J=7.7, 1.2 Hz),     -   8.68 (1H, br s).

EIMS m/z (relative intensity): 533 (M⁺), 249 (100).

Example 79 Compound No. 857 in Table Production of 8-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 72 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless neddle crystal.

Melting point: 107-108° c.

IR (KBr) cm⁻¹: 3239, 1664. 1559, 1526, 1456, 1428.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz),     -   1.34-1.54 (6H, m), 1.55-1.70 (2H, m),     -   1.73-1.88 (2H, m),     -   2.15-2.29 (2H, m), 2.42 (3H, s),     -   3.35 (2H, t, J=7.3 Hz),     -   3.54 (1H, sept, J=6.8 Hz),     -   3.89 (1H, sept, J=6.8 Hz),     -   6.90 (1H, s), 7.31 (1H, t, J=7.8 Hz),     -   7.42 (1H, t, J=7.8 Hz),     -   7.81 (1H, d, J=7.8 Hz), 7.90 (1H, d, J=7.8 Hz),     -   8.59 (1H, br s).

EIMS m/z (relative intensity): 547 (M⁺), 263 (100).

Example 80 Compound No. 858 in Table Production of 9-(benzothiazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 73 except that 2-mercaptobenzothiazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.

IR (Cap) cm⁻¹: 3243, 2962, 2927, 1668, 1559, 1526, 1456.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz),     -   1.28-1.50 (8H, m), 1.55-1.65 (2H, m),     -   1.80 (2H, quint, J=7.0 Hz), 2.17-2.27 (2H, m),     -   2.42 (3H, s), 3.34 (2H, t, J=7.0 Hz),     -   3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.32 (1H, td, J=7.1, 1.2 Hz),     -   7.43 (1H, td, J=7.1, 1.2 Hz),     -   7.81 (1H, dd, J=7.1, 1.2 Hz),     -   7.91 (1H, dd, J=7.1, 1.2 Hz), 8.65 (1H, br s).

EIMS m/z (relative intensity): 561 (M⁺), 277 (100).

Example 81 Compound No. 861 in Table Production of 2-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 53 except that 2-bromo-N-[2,4-bis(isopropylthio)-6-methylpyridyl]acetamide was used instead of 2-bromo-N-[2,4-bis(methylthio)-6-methylpyridyl]acetamide to obtain the desired compound as a colorless needle crystal.

Melting point: 223-224° C.

IR (KBr) cm⁻¹: 3437, 3138, 3106, 2960, 1668, 1534, 1414.

¹H-NMR (CDCl₃) δ:

-   -   1.22 (6H, d, J=6.8 Hz), 1.25 (6H, d, J=6.8 Hz),     -   2.42 (3H, s), 3.41 (1H, sept, J=6.8 Hz),     -   3.95 (1H, sept, J=6.8 Hz),     -   4.05 (2H, s), 6.69 (1H, s), 7.18 (1H, t, J=6.1 Hz),     -   7.19 (1H, t, J=6.1 Hz), 7.34 (1H, br s),     -   7.62 (1H, br s), 9.33 (1H, br s), 10.61 (1H, br s).

EIMS m/z (relative intensity): 446 (M⁺), 371 (100).

Elemental analysis: as C₂₁H₂₆N₄OS₃

calculated: C, 56.47; H, 5.87; N, 12.54.

found: C, 56.42; H, 5.87; N, 12.56.

Example 82 Compound No. 863 in Table Production of 4-(benzomidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 69 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow powdery crystal.

Melting point: 209-211° C.

IR (KBr) cm⁻¹: 3480, 3196, 2963, 1664, 1557, 1529, 1428.

¹H-NMR (d₆-DMSO) δ:

-   -   1.25 (6H, d, J=6.8 Hz), 1.28 (6H, d, J=6.8 Hz),     -   2.04 (2H, quint, J=7.1 Hz), 2.43 (3H, s),     -   2.44 (2H, t, J=7.1 Hz), 3.36 (2H, t, J=7.1 Hz),     -   3.61 (1H, sept, J=6.8 Hz),     -   3.86 (1H, sept, J=6.8 Hz),     -   6.96 (1H, s), 7.09 (1H, dd, J=7.3 , 5.4 Hz),     -   7.12 (1H, dd, J=7.3 , 5.4 Hz), 7.35 (1H, m),     -   7.49 (1H, m), 9.38 (1H, s), 12.53 (1H, s).

EIMS m/z (relative intensity): 474 (M⁺), 207 (100).

Example 83 Compound No. 864 in Table Production of 5-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 70 except that 2-mercaptobenimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 175-176° C.

IR (KBr) cm⁻¹: 3447, 3195, 2965, 1663, 1557, 1526, 1428, 1400.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz),     -   1.75-1.90 (4H, m), 2.26-2.38 (2H, m)., 2.42 (3H, s),     -   3.30 (2H, t, J=7.1 Hz), 3.54 (1H, sept, J=6.8 Hz),     -   3.88 (1H, sept, J=6.8 Hz), 6.91 (1H, s),     -   7.07 (1H, t, J=6.1 Hz), 7.08 (1H, t, J=6.1 Hz),     -   7.32 (1H, d, J=6.1 Hz), 7.46 (1H, d, J=6.1 Hz),     -   8.72 (1H, br s).

EIMS m/z (relative intensity): 488 (M⁺), 221 (100).

Example 84 Compound No. 865 in Table Production of 6-(benzimidazol-2-ylthio)-N-(2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 175-176° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.30 (6H, d, J=6.7 Hz), 1.32 (6H, d, J=6.7 Hz),     -   1.47-1.61 (2H, m), 1.62-1.72 (2H, m),     -   1.73-1.84 (2H, m), 2.18-2.35 (2H, m),     -   2.43 (3H, s), 3.21-3.33 (2H, m),     -   3.55 (1H, sept, J=6.7 Hz),     -   3.90 (1H, sept, J=6.7 Hz), 6.92 (1H, s),     -   7.03-7.12 (2H, m), 7.33 (1H, m), 7.47 (1H, m),     -   8.75 (1H, br s), 12.05 (1H, br s).

EIMS m/z (relative intensity): 502 (M⁺), 235 (100).

Example 85 Compound No. 866 in Table Production of 7-(benzoimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 71 except that 2-mercaptobenzoimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow needle crystal.

Melting point: 118-121° C.

IR (KBr) cm⁻¹: 3393, 3219, 2963, 2928, 1663, 1559, 1526, 1439.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.6 Hz), 1.32 (6H, d, J=6.8 Hz),     -   1.41-1.53 (4H, m), 1.64 (2H, quint, J=7.2 Hz),     -   1.76 (2H, quint, J=7.2 Hz), 2.18-2.33 (2H, m),     -   2.43 (3H, s),     -   3.28 (2H, t, J=7.2 Hz), 3.56 (1H, sept, J=6.6 Hz),     -   3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s),     -   7.08 (1H, t, J=5.9 Hz),     -   7.09 (1H, t, J=5.9 Hz), 7.40 (1H, d, J=5.9 Hz),     -   7.41 (1H, d, J=5.9 Hz), 8.86 (1H, br s).

EIMS m/z (relative intensity): 516 (M⁺), 399 (100).

Example 86 Compound No. 867 in Table Production of 8-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 72 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 176-171° C.

IR (KBr) cm⁻¹: 3158, 2963, 2930, 1665, 1559, 1526, 1508, 1429.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz)     -   1.32-1.50 (6H, m), 1.56-1.66 (2H, m),     -   1.74 (2H, quint, J=7.3 Hz), 2.17-2.27 (2H, m),     -   2.42 (3H, s), 3.26 (2H, t, J=7.3 Hz),     -   3.54 (1H, sept, J=6.8 Hz),     -   3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.05-7.10 (2H, m), 7.32 (1H, m),     -   7.45 (1H, m), 8.65 (1H, br s).

EIMS m/z (relative intensity): 530 (M⁺), 413 (100).

Example 87 Compound No. 868 in Table Production of 9-(benzimidazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 73 except that 2-mercaptobenzimidazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale brown powdery crystal.

Melting point: 112-114° C.

IR (KBr) cm⁻¹: 3435, 3185, 2927, 1660, 1558, 1526, 1437.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J 6.8 Hz) 1.31 (6H, d, J=6.8 Hz)     -   1.28-1.48 (8H, m), 1.52-1.65 (2H, m),     -   1.73 (2H, quint, J=7.1 Hz), 2.18-2.28 (2H, m),     -   2.42 (3H, s), 3.25 (2H, t, J=7.1 Hz),     -   3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.07 (1H, t, J=6.1 Hz),     -   7.08 (1H, t, J=6.1 Hz),     -   7.32 (1H, d, J=6.1 Hz), 7.46 (1H, d, J=6.1 Hz),     -   8.80 (1H, br s), 12.05 (1H, br s).

EIMS m/z (relative intensity): 544 (M⁺), 151 (100).

Example 88 Compound No. 1145 in Table Production of 6-(benzoxazole-2-ylthio)-N-[2-methyl-4,6-bis(methylthio)-5-pyrimidyl)hexanamide

4,6-Dihydroxy-2-methylpyrimidine (1.0 g, 7.9 mmol) was added gradualy to ice-cooled fuming nitric acid (3 ml) stirring. The mixture was stirred for 2 hours cooling with ice and for 1 hour at the room temperature, and then the precipitated crystal was filtered and dried to obtain 207 mg (yield 15%) of 4,6-dihydroxy-2-methy-5-nitropyrimidine.

This nitropyrimidine (205 mg, 1.2 mmol) was dissolved in phosphoryl chloride (1 ml) and diethylaniline (0.3 ml, 1.9 mmol) was added thereto, and the mixture was stirred for 1 hour at 100° C. and for 1 hour at 120° C. The reaction solution was added to ice and then extracted with ethyl acetate. The organic layer was washed with water add then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=20:1) to obtain 194 mg (yield 77%) of 4,6-dichloro-2-methyl-5-nitropyrimidine as a colorless needle crystal.

And then a methanol (10 mml) solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (1.0 g. 4.81 mmol) was added dropwise to a methanol (10 ml) solution of sodium thiomethoxide (780 mg, 10.6 mmol) while being cooled with ice, and after the mixture was stirred for 1 hour while being cooled with ice, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexan to obtain 609 mg (yield 55%) of 4,6-bis(methylthio)-2-methyl-5-nitropyrimidine.

Potassium carbonate (119 mg, 0.865 mmol) and pratinum dioxide (40mg, 0.18 mmol) were added to ethanol (100 ml) solution of this nitropyrimidine (100 mg, 0.43 mmol) and stirred in hydrogen. After 1.5 hours, the reaction mixture was filtered, the fltrate was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=6:1) to obtain 66 mg (yield 76%) of 5-amino-4,6-bis(methylthio)-2-methylpyrimidine.

And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 5-amino-4,6-bis(methylthio)-2-methylthiopyrimidine was used instead of 3-amino-2,4-bis(methlthio)-6-methylpyridine to obtain the desired compound as -a colorless powdery crystal.

Melting point: 148-151° C.

IR (KBr) cm⁻¹: 3440, 3245, 2929, 1660, 1530.

¹H-NMR (CDCl₃) δ:

-   -   1.43-1.55 (2H, m), 1.57-1.69 (2H, m),     -   1.72-1.84 (2H,m),     -   2.14-2.29 (2H, m), 2.38 (6H, s), 2.48 (3H, m),     -   3.28 (2H, t, J=7.3 Hz), 7.21 (1H, td, J=7.4, 1.7 Hz),     -   7.24 (1H, td, J=7.4, 1.7 Hz), 7.49 (1H, dd, J=7.4 Hz),     -   7.51 (1H, dd, J=7.4, 1.7 Hz), 8.91 (1H, br s).

EIMS m/z (relative intensity): 448 (M⁺, 100).

Example 89 Compound No. 1247 in Table Production of 2-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 207-209° C.

IR (KBr) cm⁻¹: 3435, 3235, 1673, 1509, 1433, 1329, 1130.

¹H-NMR (CDCl₃) δ:

-   -   2.32 (3H, s), 2.41 (3H, s), 2.48 (3H, s), 4.14 (2H,s),     -   6.81 (1H, s), 7.41 (1H, t, J=7.8 Hz),     -   7.52 (1H, d, J=7.8 Hz), 7.79 (1H, d, J=7.8 Hz),     -   8.46 (1H, br s).

EIMS m/z (relative intensity): 459 (M⁺), 227 (100).

Elemental analysis: as C₁₈H₁₆F₃N₃O₂S₃

Calculated: C, 47.05: H, 3.51; N, 9.14.

Found: C, 46.84; H, 3.66; N, 9.03.

Example 90 Compound No. 1250 in Table Production of 5-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 46 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 179-180° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.75-1.87 (2H, m), 1.87-2.00 (2H, m),     -   2.37 (3H, s), 2.39 (3H, s), 2.30-2.39 (2H, m),     -   2.43 (3H, s), 3.36-3.46 (2H, m), 6.84 (1H, s),     -   7.50 (1H, t, J=7.9 Hz), 7.59 (1H, d, J=7.9 Hz),     -   7.89 (1H, d, J=7.9 Hz), 8.85 (1H, br s).

EIMS m/z (relative intensity): 501 (M⁺), 200 (100).

Example 91 Compound No. 1252 in Table Production of 7-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 47 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 129-131° C.

IR (KBr) cm⁻¹: 3247, 1662, 1505, 1435, 1337, 1128.

¹H-NMR (d₆-DMSO) δ:

-   -   1.40-1.55 (4H, m), 1.60-1.71 (2H, m),     -   1.80-1.89 (2H,m),     -   2.20-2.34 (2H, m), 2.38 (3H, s), 2.40 (3H, s),     -   2.44 (3H, s), 3.37 (2H, t, J=7.1 Hz), 6.84 (1H, s),     -   7.49 (1H, t, J=7.8 Hz), 7.58 (1H, d, J=7.8 Hz),     -   7.88 (1H, d, J=7.8 Hz), 8.78 (1H, br s).

EIMS m/z (relative intensity): 529 (M⁺), 200 (100).

Example 92 Compound No. 1253 in Table Production of 8-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 48 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 115-116° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.40-1.54 (6H, m), 1.56-1.72 (2H, m),     -   1.85 (2H, quint, J=7.0 Hz), 2.18-2.36 (2H, m),     -   2.40 (3H, s),,2.43 (3H, s), 2.46 (3H, s), 3.38 (2H, t, J=7.3         Hz),     -   6.86 (1H, s), 7.51 (1H, t, J=7.5 Hz), 7.60 (1H, d, J=7.5 Hz),     -   7.90 (1H, d, J=7.5 Hz), 8.16 (1H, br s).

EIMS m/z (relative intensity): 543 (M⁺), 200 (100).

Example 93 Compound No. 1260 in Table Production of 5-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 46 except that 5-chloro-7-isopropyl-2-mercapto-4-metylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 155-156° C.

¹H-NMR.(d₆-DMSO) δ:

-   -   1.31 (6H, d, J=7.1 Hz), 1.72-1.85 (2H, m), 1.85-1.98 (2H, m),     -   2.36 (3H, s), 2.39 (3H, s), 2.32-2.40 (2H, m),     -   2.43 (3H, s), 2.46 (3H, s), 3.22 (1H, sept, J=7.1 Hz),     -   3.31-3.42 (2H, m), 6.84 (1H, s), 7.13 (1H, s), 8.73 (1H, br s).

EIMS m/z (relative intensity): 525 (M⁺:³⁷Cl), 523 (M⁺:³⁵Cl), 200 (100).

Example 94 Compound No. 1262 in Table Production of 7-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 47 except that 5-chloro-7-isopropyl-2-mercapto-4-metylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.

Melting point: 129-131° C.

IR (KBr) cm⁻¹: 3413, 3241, 2964, 2924, 1655, 1567, 1505, 1490, 1435, 1149.

¹H-NMR (d₆-DMSO) δ:

-   -   1.31 (6H, d, J=7.1 Hz), 1.40-1.55 (4H, m),     -   1.56-1.70 (2H, m),     -   1.83 (2H, quint, J=7.1 Hz), 2.30 (2H, t, J=7.1 Hz),     -   2.38 (3H, s), 2.40 (3H, s), 2.41 (3H, s), 2.46 (3H,s),     -   3.21 (1H, sept, J=7.1 Hz), 3.34 (2H, t, J=7.1 Hz),     -   6.84 (1H, s), 7.14 (1H, s), 8.51 (1H, br s).

EIMS m/z (relative intensity): 553 (M⁺:³⁷Cl), 551 (M⁺:³⁵Cl), 200 (100).

Example 95 Compound No. 1260 in Table Production of 8-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 48 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 128-131° C.

IR (KBr) cm⁻: 3423, 3231, 2929, 1662, 1504, 1489.

¹H-NMR (d₆-DMSO) δ:

-   -   1.32 (6H, d, J 7.0 Hz), 1.38-1.43 (4H, m),     -   1.49 (2H, quint, J=7.2 Hz), 1.60-1.69 (2H, m),     -   1.84 (2H, quint, J=7.2 Hz), 2.23-2.33 (2H, m),     -   2.40 (3H, s),     -   2.42 (3H, s), 2.45 (3H, s), 2.47 (3H, s),     -   3.23 (1H, sept, J=7.0 Hz), 3.35 (1H, t, J=7.2 Hz),     -   6.86 (1H, s), 7.15 (1H, s), 8.78 (1H, br s).

EIMS m/z (relative intensity): 567 (M⁺;³⁷Cl), 565 (M⁺;³⁵Cl), 200 (100).

Example 96 Compound No. 1267 in Table Production of 2-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 89 except that 3-amino-2,4-bis(ethylthio)-6-methylpyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless prism crystal.

Melting point: 182-183° C.

IR (KBr) cm⁻¹: 3435, 3244, 1663, 1508, 1432, 1332.

¹H-NMR (CDCl₃) δ:

-   -   1.16 (3H, t, J=7.4 Hz), 1.20 (3H, t, J=7.4 Hz),     -   2.42 (3H, s), 2.81 (2H, q, J=7.4 Hz),     -   3.03 (2H, q, J=7.4 Hz), 4.14(2H,s),     -   6.63 (1H, s), 7.40 (1H, t, J=7.8 Hz),     -   7.52 (1H, d, J=7.8 Hz),     -   7.68 (1H, d, J=7.8 Hz), 8.34 (1H, br s).

EIMS m/z (relative intensity): 487 (M⁺), 235 (100).

Elemental Analysis:C₂₀H₂₀F₃N₃O₂S₃

Calculated: C, 49.27; H, 4.13; N, 8.62; F, 11.69.

Found:C, 49.41; H, 4.20; N, 8.62; F, 11.59.

Example 97 Compound No. 1269 in Table Production of 4-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 57 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 148-150° C.

IR (KBr) cm⁻¹: 3439, 3256, 2975, 2929, 1656, 1509, 1433, 1332, 1125.

¹H-NMR (d₆-DMSO) δ:

-   -   1.23 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz),     -   2.04-2.22 (2H, m), 2.42 (3H, s),     -   2.47-2.48 (2H, m), 2.92 (2H, q, J=7.3 Hz),     -   3.04 (2H, q, J=7.3 Hz), 3.42-3.51 (2H, m),     -   6.87(1H,s),     -   7.51 (1H, t, J=7.8 Hz) 7.59 (1H, d, J=7.8 Hz),     -   7.89 (1H, d, J=7.8 Hz), 8.95 (1H, br s).

EIMS m/z (relative intensity): 515 (M⁺), 227 (100).

Example 98 Compound No. 1270 in Table Production of 5-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 58 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 155-156° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.20-1.30 (6H, m), 1.73-2.05 (4H, m),     -   2.30-2.41 (2H, m), 2.42 (3H, s),     -   2.85-3.00 (2H, m), 3.01-3.09 (2H, m),     -   3.37-3.48 (2H, m), 6.88 (1H, s),     -   7.51 (1H, t, J=7.5 Hz), 7.60 (1H, d, J=7.5 Hz),     -   7.90 (1H, d, J=7.5 Hz), 8.75 (1H, br s).

EIMS m/z (relative intensity): 529 (M⁺), 227 (100).

Example 99 Compound No. 1272 in Table Production of 7-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 59 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 127-128° C.

IR (KBr) cm⁻¹: 3448, 1659. 1506, 1336, 1128. 1116.

¹H-NMR (d₆-DMSO) δ:

-   -   1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz),     -   1.39-1.56 (4H, m), 1.56-1.72 (2H, m),     -   1.78-1.91 (2H, m), 2.19-2.33 (2H, m),     -   2.42 (3H, s), 2.92 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz), 3.37 (2H, t, J=7.2 Hz),     -   6.86 (1H, s), 7.49 (1H, t, J=7.9 Hz),     -   7.58 (1H, d, J=7.9 Hz),     -   7.88 (1H, d, J=7.9 Hz), 8.67 (1H, br s).

EIMS m/z (relative intensity): 557 (M⁺), 227 (100).

Example 100 Compound No. 1273 in Table Production of 8-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 60 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless crystal.

Melting point: 99-100° C.

IR (KBr) cm⁻¹: 3425, 3245, 2923, 1655, 1509, 1433, 1332, 1125.

¹H-NMR (d₆-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H,.t, J=7.3 Hz),     -   1.38-1.43 (4H, m), 1.49 (2H, quint, J=7.2 Hz),     -   1.60-1.68 (2H, m), 1.85 (2H, quint, J=7.2 Hz),     -   2.20-2.30 (2H, m), 2.43 (3H, s),     -   2.94 (2H, q, J=7.3 Hz),     -   3.06 (2H, q, J=7.3 Hz), 3.38 (2H, t, J=7.2 Hz),     -   6.88 (1H, s), 7.51 (1H, t, J=7.8 Hz),     -   7.60 (1H, d, J=7.8 Hz),     -   7.90 (1H, d, J=7.8 Hz), 8.73 (1H. br s).

EIMS m/z (relative intensity): 571 (M⁺), 227 (100).

Example 101 Compound No. 1274 in Table Production of 9-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 28 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 115-116° C.

¹H-NMR (d6-DMSO) δ:

-   -   1.26 (3H, t, J=7.2 Hz), 1.27 (3H, t, J 7.2 Hz),     -   1.31-1.55 (8H, m), 1.57-1.69 (2H, m),     -   1.84 (2H, quint, J=6.9 Hz), 2.18-2.34 (2H, m),     -   2.43 (3H, s), 2.94 (2H, q, J=7.2 Hz),     -   3.06 (2H, q, J=7.2 Hz),     -   3.37 (2H, t, J=7.3 Hz), 6.88 (1H, s),     -   7.51 (1H, t, J=8.4 Hz),     -   7.61 (1H, d, J=8.4 Hz), 7.90 (1H, d, J=8.4 Hz),     -   8.73 (1H, br s).

EIMS m/z (relative intensity): 585 (M⁺), 227 (100).

Example 102 Compound No. 1279 in Table Production of 4-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 57 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 122-123° C.

IR (KBr) cm⁻¹: 3258, 1665, 1502, 1145.

¹H-NMR (d₆-DMSO) δ:

-   -   1.23 (3H, t, J=7.3 Hz), 1.24 (3H, t, J=7.3 Hz),     -   1.31 (6H, d, J=6.8 Hz), 2.15 (2H, t, J=7.0 Hz),     -   2.42 (3H, s), 2.46 (3H, s), 2.47-2.50 (2H, m),     -   2.92 (2H, q, J=7.3 Hz),     -   3.04 (2H, q, J=7.3 Hz), 3.22 (1H, sept, J=6.8 Hz),     -   3.43 (2H, t, J=7.0 Hz), 6.87 (1H, s), 7.14(1H, s),     -   8.83 (1H, br s).

EIMS m/z (relative intensity): 559 (M⁺:³⁷Cl), 557 (M⁺:³⁵Cl), 227 (100).

Example 103 Compound No. 1280 in Table Production of 5-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 58 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 141-142° C.

¹H-NMR (d6-DMSO) δ:

-   -   1.25(3H, t, J=7.4 Hz), 1.26 (3H, t, J=7.4 Hz),     -   1.32 (6H, d, J=6.9 Hz), 1.75-1.86 (2H, m),     -   1.87-2.00 (2H, m), 2.30-2.40 (2H, m), 2.43 (3H,s),     -   2.45-2.52 (3H, s), 2.92 (2H, q, J=7.4 Hz),     -   3.04 (2H, q, J=7.4 Hz), 3.23 (1H, sept, J=6.9 Hz),     -   3.33-3.43 (2H, m), 6.88 (1H, s), 7.15 (1H, s), 8.82 (1H, br s).

EIMS m/z (relative intensity): 553 (M⁺;³⁷Cl), 551 (M⁺;³⁵Cl), 227 (100).

Example 104 Compound No. 1282 in Table Production of 7-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 59 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.

Melting point: 117-120° C.

IR (KBr) cm⁻¹: 3320, 1668, 1506, 1482, 1150.

¹H-NMR (d₆-DMSO) δ:

-   -   1.24 (3H, t, J=7.3 Hz), 1.25 (3H, t, J=7.3 Hz),     -   1.31 (6H, d, J=6.8 Hz), 1.39-1.57 (4H, m),     -   1.57-1.71 (2H, m),     -   1.77-1.89 (2H, m), 2.19-2.30 (2H, m), 2.42 (3H,s),     -   2.46 (3H, s), 2.92 (2H, q, J=7.3 Hz),     -   3.05 (2H, q, J=7.3 Hz),     -   3.21 (1H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.2 Hz),     -   6.86 (1H, s), 7.13 (1H, s), 8.66 (1H, br s).

EIMS m/z (relative intensity): 581 (M⁺:³⁷Cl), 579 (M⁺:³⁵Cl), 227 (100).

Example 105 Compound No. 1283 in Table Production of 8-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 60 except that 5-chloro-7-isoprdpyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 82-84° C.

IR (KBr) cm⁻¹: 3435, 3259, 2929, 1655, 1504, 1490.

¹H-NMR (d₆-DMSO) δ:

-   -   1.26 (3H, t, J=7.3 Hz), 1.27 (3H, t, J=7.3 Hz),     -   1.32 (6H, d, J=6.8 Hz), 1.39-1.43 (4H, m),     -   1.49 (2H, quint, J=7.2 Hz), 1.60-1.68 (2H, m),     -   1.84 (2H, quint, J=7.2 Hz), 2.22-2.32 (2H, m), 2.43 (3H, s),     -   2.47 (3H, s), 2.94 (2H, q, J=7.3 Hz), 3.06 (2H, q, J=7.3 Hz),     -   3.22 (1H, sept, J=6.8 Hz), 3.35 (2H, t, J=7.2 Hz),     -   6.88 (1H, s), 7.15 (1H, s), 8.73 (1H, br s).

EIMS m/z (relative intensity): 595 (M⁺;³⁷Cl), 593 (M⁺;³⁵Cl),

Example 106 Compound No. 1284 in Table Production of 9-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 28 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless powdery crystal.

Melting point: 93-94° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (3H, t, J=7.3 Hz), 1.28 (3H, t, J 7.3 Hz),     -   1.32 (6H, d, J=7.0 Hz), 1.29-1.55 (8H, m),     -   1.56-1.69 (2H, m), 1.83 (2H, quint, J=6.9 Hz),     -   2.07-2.17 (2H, m), 2.43 (3H, s),     -   2.45-2.49 (3H, m), 2.94 (2H, q, J=7.3 Hz),     -   3.07 (2H, q, J=7.3 Hz), 3.22 (1H, sept, J=7.0 Hz),     -   3.34 (2H, t, J=7.3 Hz), 6.88 (1H_(,) s), 7.15 (1H, s),     -   8.73 (1H, br s).

EIMS m/z (relative intensity): 609 (M⁺;³⁷Cl), 607 (M⁺;³⁵Cl), 229 (100).

Example 107 Compound No. 1287 in Table Production of 2-(7-triffluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 89 except that 2-bromo-N-[2,4-bis(isopropylthio)-6-methylpyridyl]amide was used instead of 2-bromo-[2,4-bis(methylthio)-6-methylpyridyl]acetamide to obtain the desired compound as a colorless needle crystal.

Melting point: 121-122° C.

IR (KBr) cm⁻¹: 3426, 3210, 2967, 1655, 1507, 1431, 1329.

¹H-NMR (CDCl₃) δ:

-   -   1.17 (6H, d, J=6.8 Hz), 1.19 (6H, d, J=6.8 Hz),     -   2.42 (3H, s),     -   3.39 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz),     -   4.13 (2H, s), 6.68 (1H, s), 7.41 (1H, t, J=7.9 Hz),     -   7.52 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=7.9 Hz),     -   8.30 (1H, br s).

EIMS m/z (relative intensity): 515 (M⁺), 181 (100).

Elemental analysis: as C₂₂H₂₄F₃N₃O₂S₃

Calculated: C, 51.25; H, 4.69; N, 8.15; F, 11.05.

Found: C, 51.28; H, 4.73; N, 8.07; F, 11.02.

Example 108 Compound No. 1289 in Table Production of 4-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 69 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless prism crystal.

Melting point: 135-136° C.

IR (KBr) cm⁻¹: 3446, 3255, 2968, 1660, 1559, 1531, 1504, 1491, 1433, 1139.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J=6.8 Hz), 1.29 (6H, d, J=6.8 Hz),     -   2.13-2.21 (2H, m), 2.42 (3H, s),     -   2.47-2.50 (2H, m), 3.44-3.50 (2H, m),     -   3.55 (1H, sept, J=6.8 Hz), 3.88 (1H, sept, J=6.8 Hz),     -   6.92 (1H, s), 7.51 (1H, t, J=7.8 Hz),     -   7.59 (1H, d, J=7.8 Hz),     -   7.88 (1H, d, J=7.8 Hz), 8.91 (1H, br s).

EIMS m/z (relative intensity): 543 (M⁺), 207 (100).

Example 109 Compound No. 1290 in Table Production of 5-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 70 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 118-120° C.

IR (KBr) cm⁻¹: 3208, 3163, 1663, 1506, 1431, 1328, 1139.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz),     -   1.73-1.87 (2H, m), 1.87-2.01 (2H, m),     -   2.23-2.38 (2H, m), 2.41 (3H, s),     -   3.41 (2H, t, J=7.0 Hz), 3.54 (1H, sept, J=6.8 Hz),     -   3.88 (1H, sept, J=6.8 Hz), 6.91 (1H, s),     -   7.49 (1H, t, J=7.9 Hz),     -   7.58 (1H, d, J=7.9 Hz), 7.88 (1H, d, J=7.9 Hz).     -   8.67 (1H, br s).

EIMS m/z (relative intensity): 557 (M⁺), 221 (100).

Example 110 Compound No. 1291 in Table Production of 6-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 102-103° C.

IR (KBr) cm⁻¹: 3136, 1648, 1507, 1431, 1332, 1129.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz),     -   1.49-1.76 (4H, m), 1.77-1.94 (2H, m),     -   2.19-2.32 (2H, m), 2.42 (3H, s), 3.38 (2H, t, J=7.3 Hz),     -   3.55 (1H, sept, J=6.8 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.49 (1H, t, J=7.8 Hz), 7.58 (1H, d, J=7.8 Hz),     -   7.87 (1H, d, J=7.8 Hz), 8.62 (1H, br s).

EIMS m/z (relative intensity): 571 (M⁺), 235 (100).

Example 111 Compound No. 1292 in Table Production of 7-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 71 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzothiazole to obtain the desired compound as a colorless crystal.

Melting point: 76-78° C.

IR (KBr) cm⁻¹: 3423, 3268, 2931, 1660, 1506, 1433, 1334.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz),     -   1.43-1.54 (4H, m), 1.61-1.69 (2H, m),     -   1.86 (2H, quint, J=7.2 Hz), 2.18-2.32 (2H, m),     -   2.43 (3H, s), 3.39 (2H, t, J=7.2 Hz),     -   3.56 (1H, sept, J=6.8 Hz),     -   3.90 (1H, sept, J=6.8 Hz), 6.93 (1H, s),     -   7.51 (1H, dd, J=8.1, 7.8 Hz), 7.60 (1H, d, J=7.8 Hz),     -   7.90 (1H, d, J=8.1 Hz), 8.68 (1H, br s).

EIMS m/z (relative intensity): 585 (M⁺), 249 (100).

Example 112 Compound No. 1293 in Table Production of 8-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 72 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.

IR (Cap) cm⁻¹: 3246, 2964, 2930, 1664, 1559, 1506, 1432.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz), 1.30 (6H, d, J=6.8 Hz),     -   1.32-1.50 (6H, m), 1.56-1.66 (2H, m),     -   1.83 (2H, quint, J=7.1 Hz), 2.17-2.27 (2H, m),     -   2.42 (3H, s), 3.36 (2H, t, J=7.1 Hz),     -   3.55 (1H, sept, J=6.8 Hz),     -   3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.50 (1H, t, J=7.8 Hz),     -   7.59 (1H, d, J=7.8 Hz),     -   7.88 (1H, d, J=7.8 Hz), 8.65 (1H, br s).

EIMS m/z (relative intensity): 599 (M⁺), 263 (100)

Example 113 Compound No. 1294 in Table Production of 9-(7-trifluoromethylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 73 except that 2-mercapto-7-trifluoromethylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale-yellow powdery crystal.

Melting point: 97-98° C.

IR (KBr) cm⁻¹: 3446, 3266, 2928, 1661, 1560, 1506, 1335, 1127.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.6 Hz), 1.30 (6H, d, J 6.8 Hz)     -   1.28-1.51 (8H, m), 1.55-1.64 (2H, m),     -   1.83 (2H, quint, J=7.3 Hz), 2.20-2.30 (2H, m),     -   2.42 (3H, s), 3.36 (2H, t, J=7.3 Hz),     -   3.55 (1H, sept, J=6.6 Hz), 3.89 (1H, sept, J=6.8 Hz),     -   6.91 (1H, s), 7.50 (1H, t, J=7.8 Hz),     -   7.59 (1H, d, J=7.8 Hz),     -   7.89 (1H, d, J=7.8 Hz), 8.71 (1H, br s).

EIMS m/z (relative intensity): 613 (M⁺), 277 (100).

Example 114 Compound No. 1299 in Table Production of 4-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]butanamide

The reaction and the treatment were conducted in the same manner as in Example 69 except that 5-chloro-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 141-143° C.

¹H-NMR (d₆-DMSO) δ:

-   -   1.27 (6H, d, J=6.8 Hz), 1.29 (6H, d, J=6.8 Hz),     -   1.31 (6H, d, J=6.8 Hz), 2.03-2.21 (2H, m),     -   2.42 (3H, s), 2.43-2.50 (5H, m),     -   3.22 (1H, sept, J=6.8 Hz),     -   3.38-3.48 (2H, m), 3.55 (1H, sept, J=6.8 Hz),     -   3.88 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.14 (1H,s),     -   8.87 (1H, br s).

EIMS m/z (relative intensity): 567 (M⁺:³⁷Cl), 565 (M⁺:³⁵Cl), 207 (100).

Example 115 Compound No. 1300 in Table Production of 5-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]pentanamide

The reaction and the treatment were conducted in the same manner as in Example 70 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 143-145° C.

IR (KBr) cm⁻¹: 3231, 2924, 1720, 1657, 1508, 1297

¹H-NMR (d6-DMSO) δ:

-   -   1.27 (6H, d, J=6.8 Hz), 1.29 (6H, d, J=6.8 Hz),     -   1.31 (6H, d, J=6.8 Hz), 1.73-1.85 (2H, m),     -   1.85-1.98 (2H, m),     -   2.25-2.37 (2H, m), 2.41 (3H, s),     -   2.43-2.50 (3H, s), 3.21 (1H, sept, J=6.8 Hz),     -   3.37 (2H, t, J=7.2 Hz), 3.54 (1H, sept, J=6.8 Hz),     -   3.88 (1H, sept, J=6.8 Hz), 6.92 (1H, s), 7.14 (1H,s),     -   8.76 (1H, br s).

EIMS m/z (relative intensity): 581 (M⁺:³⁷Cl), 579 (M⁺:³⁵Cl, 100)

Example 116 Compound No. 1301 in Table Production of 6-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 36 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 99-101° C.

IR (KBr) cm⁻¹: 3413, 3224, 2964, 1663, 1506, 1148.

¹H-NMR (d6-DMSO) δ:

-   -   1.29 (6H, d, J=6.8 Hz), 1.32 (12H, d, J=6.8 Hz),     -   1.54-1.62 (2H, m), 1.70 (2H, quint, J=7.1 Hz),     -   1.87 (2H, quint, J=7.1 Hz), 2.22-2.33 (2H, m),     -   2.43 (3H, s), 2.48 (3H, s),     -   3.23 (1H, sept, J=6.8 Hz), 3.36 (2H, t, J=7.1 Hz),     -   3.57 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz),     -   6.93 (1H, s), 7.15 (1H, s), 8.72 (1H, br s).

EIMS m/z (relative intensity): 595 (M⁺;³⁷Cl), 593 (M⁺:³⁵Cl), 518 (100)

Example 117 Compound No. 1302 in Table Production of 7-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]heptanamide

The reaction and the treatment were conducted in the same manner as in Example 71 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 91-93° C.

IR (KBr) cm⁻¹: 3436, 3213, 3169, 2962, 2929, 1666, 1505, 1152.

¹H-NMR (d₆-DMSO) δ:

-   -   1.29 (6H, d, J=6.8 Hz), 1.31 (6H, d, J=6.8 Hz),     -   1.31 (6H, d, J=6.8 Hz), 1.40-1.52 (4H, m),     -   1.60-1.68 (2H, m), 1.85 (2H, quint, J=7.1 Hz),     -   2.17-2.32 (2H, m), 2.43 (3H, s),     -   2.47 (3H, s), 3.22 (1H, sept, J=6.8 Hz),     -   3.35 (2H, t, J=7.1 Hz),     -   3.56 (1H, sept, J=6.8 Hz), 3.90 (1H, sept, J=6.8 Hz),     -   6.93 (1H, s), 7.15 (1H, s), 8.67 (1H, br s).

EIMS m/z (relative intensity): 609 (M⁺;³⁷Cl), 607 (M⁺;³⁵Cl), 532 (100).

Example 118 Compound No. 1303 in Table Production of 8-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]octanamide

The reaction and the treatment were conducted in the same manner as in Example 72 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.

IR (Cap) cm⁻¹: 3242, 2964, 2928, 1668, 1559, 1506, 1148.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.6 Hz), 1.31 (12H, d, J=6.8 Hz),     -   1.32-1.50 (6H, m), 1.57-1.67 (2H, m),     -   1.82 (2H, quint, J=7.1 Hz), 2.17-2.27 (2H, m),     -   2.42 (3H, s), 2.46 (3H, s), 3.21 (1H, sept, J=6.8 Hz),     -   3.33 (2H, t, J=7.1 Hz), 3.55 (1H, sept, J=6.6 Hz),     -   3.89 (1H, sept, J=6.8 Hz), 6.91 (1H, s),     -   7.14 (1H, s), 8.65 (1H, br s).

EIMS m/z (relative intensity): 623 (M⁺:³⁷Cl), 621 (M⁺:³⁵Cl) 546 (100).

Example 119 Compound No. 1304 in Table Production of 9-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]nonanamide

The reaction and the treatment were conducted in the same manner as in Example 73 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzoxazole to obtain the desired compound as a pale yellow oil.

IR (Cap) cm⁻¹: 3249, 2961, 2926, 1667, 1563, 1505.

¹H-NMR (d₆-DMSO) δ:

-   -   1.28 (6H, d, J=6.8 Hz), 1.30 (12H, d, J=7.1 Hz)     -   1.28-1.50 (8H, m), 1.55-1.65 (2H, m),     -   1.81 (2H, quint, J=7.1 Hz), 2.17-2.27 (2H, m),     -   2.41 (3H, s), 2.46 (3H, s), 3.21 (1H, sept, J=7.1 Hz),     -   3.32 (2H, t, J=7.1 Hz), 3.54 (1H, sept, J=6.8 Hz),     -   3.89 (1H, sept, J=7.1 Hz), 6.91 (1H, s),     -   7.14 (1H, s), 8.65 (1H, br s).

EIMS m/z (relative intensity): 637 (M⁺:³⁷Cl), 635 (M⁺:²⁵Cl) 560 (100).

Example 120 Compound No. 1317 in Table Production of 2-(7-methansulfonylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 96 except that 2-mercapto-7-methansulfonylbenzoxazole was used instead of 2-mercapto-7-trifluoromethylbenzoxazole to obtain the desired compound as a colorless needle crystal.

Melting point: 159-162° C.

IR (KBr) cm⁻¹: 3449, 3271, 2966, 2928, 1678, 1508, 1315, 1118.

¹H-NMR (CDCl₃) δ:

-   -   1.14 (3H, t, J=7.3 Hz), 1.20 (3H, t, J=7.3 Hz),     -   2.43 (3H, s),     -   2.82 (2H, q, J=7.3 Hz), 3.01 (2H, q, J=7.3 Hz),     -   3.27 (2H, s),     -   4.15 (2H, s), 6.63 (1H, s), 7.49 (1H, t, J=7.9 Hz),     -   7.83 (1H, dd, J=7.9 , 1.2 Hz), 7.90 (1H, dd, J=7.9, 1.2 Hz),     -   8.17 (1H, br s).

EIMS m/z (relative intensity): 497 (M⁺), 311 (100).

Elemental analysis: as C₂₀H₂₃N₃O₄S₄

Calculated: C, 48.27; H, 4.66; N, 8.44; S, 25.77.

Found: C, 48.36; H, 4.66; N, 8.31; S, 25.76.

Example 121 Compound No. 1327 in Table Production of 2- (7-methansulfonylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 74 except that 2-mercapto-7-methansulfonylbenzoxazole was used instead of 2-mercaptobenzothiazole to obtain the desired compound as a pale yellow amorphous.

IR (KBr) cm⁻¹: 3435, 3337, 2965, 2926, 1695, 1506, 1424, 1319, 1117.

¹H-NMR (CDCl₃) δ:

-   -   1.16 (6H, d, J=6.8 Hz), 1.21 (6H, d, J=6.8 Hz),     -   2.42 (3H, s),     -   3.26 (3H, s), 3.40 (1H, sept, J=6.8 Hz),     -   3.90 (1H, sept, J=6.8 Hz), 4.15 (2H, s), 6.68 (1H,s),     -   7.49 (1H, t, J=7.9 Hz), 7.83 (1H, dd, J=7.9 , 1.0 Hz),     -   7.90 (1H, dd, J=7.9 , 1.0 Hz), 8.11 (1H, br s).

EIMS m/z (relative intensity): 525 (M⁺), 339 (100).

Example 122 Compound No. 1341 in Table Production of 6-(benzoxasole-2-ylthio)-N-(4-methyl-2-(methylthio)-5-pyridyl)hexanamide

A methanol (8 mml) solution of 2-dichloro-4-methyl-5-nitropyrimidine (2.0 g. 10.4 mmol) was added dropwise to a methanol (8 ml) solution of sodium thiomethoxide (436 mg, 5.9 mmol) while being cooled with ice, and after the mixture was stirred for 15 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexan to obtain 1.02 g (yield 98%) of 4-methyl-2-methylthio-5-nitropyridine as a pale-yellow needle crystal.

This nitropyridine (497 mg, 2.7 mmol) was dissolved in a mixed solvent of acetic acid (15 ml) and conc. hydrochloric acid (0.5 ml), and zinc (2.12 g, 32.4 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 30 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=1:1) to obtain 352 mg (yield 85%) of 5-amino-4-methyl-2-methylthiopyridine as a pale-yellow powdery crystal.

And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 5-amino-4-methyl-2-methylthiopyridine was used instead of 3-amino-2,4-bis(methlthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.

Melting point: 125-127° C.

IR (KBr) cm⁻¹: 3433, 3284, 2930, 1654, 1598.

¹H-NMR (CDCl₃) δ:

-   -   1.61 (2H, quint, J=7.4 Hz),     -   1.83 (2H, quint, J=7.4 Hz),     -   1.92 (2H, quint, J=7.4 Hz), 2.19 (3H, s),     -   2.43 (2H, t, J=7.4 Hz), 2.54 (3H, s),     -   3.33 (2H, t, J=7.4 Hz),     -   6.92 (1H, br s), 7.03 (1H, s),     -   7.24 (1H, td, J=7.7, 1.7 Hz),     -   7.28 (1H, td, J=7.7, 1.7 Hz),     -   7.43 (1H, dd,,J=7.7, 1.7 Hz),     -   7.57 (1H, dd, J=7.7, 1.7 Hz), 8.57 (1H, s).

EIMS m/z (relative intensity): 401 (M⁺), 69 (100).

Example 123 Compound No. 1371 in Table Production of 6-(benzoxasole-2-ylthio)-N-(5-methylthio-2-pyridyl)hexanamide

After conc. sulfuric acid (50 ml) was cooled with ice, 30% aqueous solution of hydrogen peroxide (25 ml) was dropped thereto stirring, and then conc. sulfuric acid (50 ml) solution of 2-amino-5-chloropyridine (5.0 g, 38.9 mmol) was dropped thereto further and stirred for 48 hours at the room temperature. The reaction mixture was added into ice and filtered. The residue was recrystallized with ethanol to obtain 4.38 g (yield 71 %) of 5-chloro-2-nitoropyriine as a colorless powdery crystal.

A methanol (40 mml) solution of 5-chloro-2-nitropyridine (2.0 g. 12.6 mmol) was added dropwise to a methanol (20 ml) solution of sodium thiomethoxide (1.02 g, 13.9 mmol) while being cooled with ice, and after the mixture was stirred for 13 hours while raising its temperature to the room temperature, water added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was recrystalized with ethyl acetate-hexane to obtain 972 mg (yield 45%) of 5-methylthio-2-nitropyridine.

This nitropyridine (300 mg, 1.8 mmol) was dissolved in a mixed solvent of acetic acid (7 ml) and conc. hydrochloric acid (0.5 ml), and zinc (692 g, 10.6 mmol) was added thereto in small portions while being cooled with ice for 5 minutes. After the mixture was stirred for 30 minutes at the room temperature, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Thereafter, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (eluent—hexane:ethyl acetate=1:1→chloroform:methanol=20:1) to obtain 158 mg (yield 64%) of 2-amino-5-methylthiopyridine as a pale-yellow powdery crystal.

And then the reaction and the treatment were conducted in the same manner as in Example 18 except that 2-amino-5-methylthiopyridine was used instead of 3-amino-2,4-bis(methlthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.

Melting point: 83-85° C.

IR (KBr) cm⁻: 3246, 2930, 1684, 1576, 1522.

¹H-NMR (CDCl₃) δ:

-   -   1.59 (2H, quint, J=7.4 Hz),     -   1.81 (2H, quint, J=7.4 Hz),     -   1.90 (2H, quint, J=7.4 Hz), 2.42 (2H, t, J 7.4 Hz),     -   2.48 (3H, s), 3.32 (2H, t, J=7.4 Hz),     -   7.23 (1H, td, J=7.4, 1.4 Hz),     -   7.28 (1H, td, J=7.4, 1.4 Hz),     -   7.43 (1H, dd, J=7.4, 1.4 Hz),     -   7.59 (1H, dd, J=7.4, 1.4 Hz),     -   7.64 (1H, dd, J=8.6 , 2.5 Hz), 7.82 (1H, br s),     -   8.15 (1H, d, J=8.6 Hz), 8.18 (1H, d, J=2.5 Hz).

EIMS m/z (relative intensity): 387 (M⁺, 100).

Example 124 Compound No. 1401 in Table Production of 6-(benzoxazol-2-ylthio)-N-[2,4,6-tris(methylthio)-5-pyrimidyl]hexanamide

The reaction and the treatment were conducted in the same manner as in Example 88 except that 4,6-dihydroxy-2-methylthiopyrimidine was used instead of 4,6-dihydroxy-2-methylpyrimidine to obtain the desired compound as a colorless powdery crystal.

Melting point: 149-153° C.

IR (KBr) cm⁻¹: 3448, 3247, 2926, 1667, 1496.

¹H-NMR (CDCl₃) δ:

-   -   1.46-1.62 (2H, m), 1.63-1.76 (2H, m),     -   1.77-1.91 (2H, m), 2.20-2.36 (2H, m),     -   2.46 (9H, s), 3.36 (2H, t, J=7.1 Hz),     -   7.22-7.35 (2H, m), 7.51-7.62 (2H, m),     -   9.02 (1H, bras).

EIMS m/z (relative intensity): 480 (M⁺, 100).

Example 125 Compound No. 1427 in Table Production of 2-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 26 except that 2-mercapto-7-methoxycarbonylbenzoxazole was used instead of 2-mercaptobenzoxasole to obtain the desired compound as a colorless needle crystal.

Melting point: 168-169° C.

IR (KBr) cm⁻¹: 3433, 3257, 1727, 1677, 1513, 1297, 1120.

¹H-NMR (CDCl₃) δ:

-   -   1.16 (3H, t, J=7.4 Hz), 1.19 (3H, t, J=7.4 Hz),     -   2.42 (3H, s), 2.80 (2H, q, J=7.4 Hz),     -   3.03 (2H, q, J=7.4 Hz), 4.00 (3H, s),     -   4.12 (2H, s), 6.63 (1H, s),     -   7.38 (1H, dd, J=8.1,7.8 Hz),     -   7.80 (1H, dd, J=8.1, 1.2 Hz),     -   7.92 (1H, dd, J=7.8 , 1.2 Hz),     -   8.48 (1H, br s).

EIMS m/z (relative intensity): 477 (Me), 323 (100).

Elemental analysis: as C₂₁H₂₃N₃O₄S₃

Calculated: C, 52.81; H, 4.85; N, 8.80; S, 20.14.

Found: C, 52.90; H, 4.91; N, 8.73; S, 20.12.

Example 126 Compound No. 1428 in Table Production of 2-(oxazolo[4,5-b]pyridine-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 49 except that 2-mercaptoxazolo[4,5-b]pyridine was used instead of 2-mercaptobenzoxasole to obtain the desired compound as a colorless crystal.

IR (KBr) cm⁻¹: 34,60, 3167, 2972, 1685, 1561.

¹H-NMR (CDCl₃) δ:

-   -   1.14 (3H, t, J=7.4 Hz), 1.21 (3H, t, J=7.4 Hz),     -   2.42 (3H, s), 2.82 (2H, q, J 7.4 Hz),     -   3.02 (2H, q, J=7.4 Hz), 4.16 (2H, s), 6.62 (1H, s),     -   7.25 (1H, dd, J=8.3, 5.1 Hz),     -   7.78 (1H, dd, J=8.3, 1.2 Hz),     -   8.40 (1H, br s), 8.49 (1H, dd, J=5.1, 1.2 Hz).

EIMS m/z (relative intensity): 420 (M⁺, 100).

Example 127 Compound No. 1257 in Table Production of 2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 49 except that 5-chloro-7-isopropyl-2-mercapto-4-methylbenzoxazole was used instead of 2-mercaptobenzothiazole to obtain the desired compound as a colorless powdery crystal.

EIMS m/z (relative intensity): 481 (M⁺), 210 (100).

Example 128 Compound No. 1277 in Table Production of 2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(ethylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 127 except that 3-amino-2,4-bis(isopropylthio)-6-methylpyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.

EIMS m/z (relative intensity): 511 (M⁺;³⁷Cl), 509 (M⁺;³⁵Cl), 235 (100).

Example 129 Compound No. 1297 in Table Production of 2-(5-chloro-7-isopropyl-4-methylbenzoxazol-2-ylthio)-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide

The reaction and the treatment were conducted in the same manner as in Example 127 except that 3-amino-2,4-bis(isopropylthio)-6-methylpyridine was used instead of 3-amino-2,4-bis(methylthio)-6-methylpyridine to obtain the desired compound as a colorless powdery crystal.

EIMS m/z (relative intensity): 539 (M⁺;³⁷Cl), 537 (M⁺;³⁵Cl), 223 (100). 

1-8. (canceled)
 9. Compounds represented by the formula (I)

wherein

represents an optionally substituted divalent residue of benzene, cyclohexane or naphthalene, or a group:

Het represents a substituted pyridyl group; X represents —NH—; Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₄ represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and n is an integer of from 1 to 15 (except that n is 1), or salts or solvates thereof.
 10. The compounds according to claim 9, which are represented by the formula (IA)

wherein

represents an optionally substituted divalent residue of benzene; Py represents a substituted pyridyl group; X represents —NH—; Y represents —NR₄,—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₄, represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and n is an integer of from 1 to 15 (except that n=1); or salts or solvates thereof.
 11. The compounds according to claim 9, which are represented by the formula (III)

wherein, W represents ═CH—; X represents —NH—; Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₁, R₂, and R₃, are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a phosphate group, a sulfonamide group, a lower alkylthio group or an optionally substituted amino group, or two of R₁, R₂, and R₃, together form an alkylenedioxide group (except that R₁, R₂ and R₃, all are a hydrogen); R₄, represents a hydrogen atom, a lower alkyl group, an aryl group ar an optionally substituted silyl lower alkyl group; and n is an integer of from 1 to 15 (except that n is 1), or salts or solvates thereof.
 12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound selected from the compounds represented by the formula (I)

wherein

represents an optionally substituted divalent residue of benzene, cyclohexane or naphthalene, or a group:

Het represents a substituted pyridyl group; X represents —NH—; Y represents —NR,-, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₄, represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and n is an integer of from 1 to 15 (except that n is 1), or salts or solvates thereof.
 13. The pharmaceutical composition according to claim 12, which is an ACAT inhibitor, an intracellular cholesterol transfer inhibitor, a blood cholesterol depressant or a macrophage foamation suppressant.
 14. The pharmaceutical composition according to claim 12, which is a remedy or a medication for preventing hyperlipemia, arteriosclerosis, cerebrovascular accidents, ischemic heart disease, ischemic intestinal disease or aortic aneurysm.
 15. The pharmaceutical composition according to claim 13, which is a remedy or a medication for preventing hyperlipemia, arteriosclerosis, cerebrovascular accidents, ischemic heart disease, ischemic intestinal disease or aortic aneurysm.
 16. The method for treating hyperlipemia, arteriosclerosis, cerebrovascular accidents, ischemic heart disease, ischemic intestinal disease or aortic aneurysm in need of such treatment using compounds of the formula (I′)

wherein

represents an optionally substituted divalent residue of benzene, cyclohexane or naphthalene, or a group:

Het represents substituted or unsubstituted pyridyl group; X represents —NH—; Y represents —NR₄,-, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₄, represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and n is an integer of from 1 to 15; or salts or solvates thereof.
 17. The method of claim 16 using compounds of the formula (I′A)

wherein

represents an optionally substituted divalent residue of benzene; Py represents an optionally substituted pyridyl group; X represents —NH—; Y represents —NR₄—, an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₄ represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; n is an integer of from 1 to 15, or salts or solvates thereof.
 18. The method of claim 16 using compounds of the formula (III′)

wherein, Wrepresents ═CH—, x represents —NH—; Y represents —NR₄— an oxygen atom, a sulfur atom, a sulfoxide or a sulfone; Z represents a single bond; R₁ R₂, and R₃, are the same or different, and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a hydroxyl group, a phosphate group, a sulfonamide group, a lower alkylthio group or an optionally substituted amino group, or two of R₁, R₂, and R₃, together form an alkylenedioxide group; R₄, represents a hydrogen atom, a lower alkyl group, an aryl group or an optionally substituted silyl lower alkyl group; and n is an integer of from 1 to 15; or salts or solvates thereof.
 19. A method claim 16 using a compound represented by the formula (I), wherein

wherein

represents an optionally substituted divalent residue of benzene; Het represents a substituted or unsubstituted pyridyl group; X is —NH—; Y is a sulfur atom; Z is a single bond; n is 1; or salts or solvates thereof. 